JP4398725B2 - Viral polymerase inhibitor - Google Patents

Abstract

An isomer, enantiomer, diastereoisomer or tautomer of a compound, represented by formula I: wherein: A is O, S, N R 1 , or C R 1 , wherein R 1 is defined herein; ----- represents either a single or a double bond; R 2 is selected from: H, halogen, R 21 , O R 21 , S R 21 , COO R 21 , SO 2 N( R 22 ) 2 , N( R 22 ) 2 , , CON( R 22 ) 2 , N R 22 C(O) R 22 or N R 22 C(O)N R 22 wherein R 21 and each R 22 is defined herein; B is N R 3 or C R 3 , with the proviso that one of A or B is either C R 1 or C R 3 , wherein R 3 is defined herein; K is N or C R 4 , wherein R 4 is defined herein; L is N or C R 5 , wherein R 5 has the same definition as R 4 ; M is N or C R 7 , wherein R 7 has the same definition as R 4 ; Y 1 is O or S; Z is N( R 6a ) R 6 or O R 6 , wherein R 6a is H or alkyl or N R 61 R 62 wherein R 61 and R 62 are defined herein; and R 6 is H, alkyl, cycloalkyl, alkenyl, Het , alkyl-aryl, alkyl- Het ; or R 6 is wherein R 7 and R 8 and Q are as defined herein; Y 2 is O or S; R 9 is H, (C 1-6 alkyl), (C 3-7 )cycloalkyl or (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het , (C 1-6 )alkyl-aryl or (C 1-6 )alkyl- Het , all of which optionally substituted with R 90 ; or R 9 is covalently bonded to either of R 7 or R 8 to form a 5- or 6-membered heterocycle; a salt or a derivative thereof, as an inhibitor of HCV NS5B polymerase.

Description

  The present invention relates to RNA-dependent PNA polymerases, in particular these viral polymerases within the Flaviviridae family, and more particularly to inhibitors of HCV polymerase.

  It is estimated that approximately 30,000 new cases of hepatitis C virus (HCV) infection occur each year in the United States (Kolykhalov, AA; Mihalik, K .; Feinstone, SM; Rice, CM; 2000; J. Virol. 74: 2046-2051). HCV is not easily removed by host immunological defenses. About 85% of people infected with HCV become chronically infected. Many of these persistent infections result in chronic liver disease, including cirrhosis and hepatocellular carcinoma (Hoofnagle, J.H .; 1997; Hepatology 26: 15S-20S *). There are an estimated 170 million HCV carriers worldwide, and HCV-related end-stage liver disease is now the most important cause of liver transplantation. In the United States alone, hepatitis C is responsible for 8,000 to 10,000 deaths annually. Without effective intervention, the number is expected to triple in the next 10-20 years. There is no vaccine to prevent HCV infection. Prolonged treatment of chronically infected patients with interferon or interferon and ribavirin is currently the only approved therapy, but it produces a sustained response in less than 50% of cases (Lindsay, KL; 1997; Hepatology 26: 71S-77S * And Reichard, O .; Schvarcz, R .; Weiland, O .; 1997 Hepatology 26: 108S-111S *).

HCV belongs to the family Flaviviridae, Hepacivirus, which includes three genera of small outer membrane positive strand RNA viruses (Rice, CM; 1996; “Flavaviridae: viruses and their replication”; Fields Virology 931-960 Page; Fields, BN; Knipe, DM; Howley, PM edit; Lippincott-Raven Publishers, Philadelphia Pa. *). The 9.6 kb genome of HCV consists of a long open reading frame (ORF) flanked by 5 'and 3' untranslated regions (NTR). HCV 5 'NTR is 341 nucleotides in length and functions as an internal ribosome entry site for cap-independent translation initiation (Lemon, SH; Honda, M .; 1997; Semin. Virol. 8: 274-288 ). The HCV polyprotein is cleaved simultaneously with translation and then into at least 10 individual polypeptides (Reed, KE; Rice, CM; 1999; Curr. Top. Microbiol. Immunol. 242: 55-84 *). The structural protein is derived from a signal peptidase in the N-terminal portion of the polypeptide. Two viral proteases mediate downstream cleavage, resulting in a nonstructural (NS) protein that functions as a component of HCV RNA replicase. NS2-3 protease spans the C-terminal half of NS2 and the N-terminal 1/3 of NS3 and catalyzes the cis cleavage of the NS2 / 3 site. The same part of NS3 also encodes the catalytic domain of NS3-4A serine protease that is cleaved at four downstream sites. NS3 C-terminal 2/3 is highly conserved among HCV isolates with RNA binding activity, RNA stimulated NTPase activity, and RNA unwinding activity. NS4B and NS5A phosphoproteins are also probably components of replicase, but their specific role is unknown. C-terminal polyprotein cleavage product, NS5B, is an extended subunit of HCV replicase with RNA-dependent RNA polymerase (RdRp) activity (Behrens, SE; Tomei, L .; DeFrancesco, R .; 1996; EMBO J. 15: 12-22 *; and Lohmann, V .; Korner, F .; Herian, U .; Bartenschlager, R .; 1997; J. Virol. 71: 8416-8428 *). Recently, mutations that impair NS5B activity have been demonstrated to abolish RNA infectivity in a chimpanzee model (Kolykhalov, AA; Mihalik, K .; Feinstone, SM; Rice, CM; 2000; J. Virol. 74: 2046-2051 *).
Development of new and specific anti-HCV therapies is a high priority, and virus-specific functions essential for replication are the most attractive targets for drug development. The absence of an RNA-dependent RNA polymerase in mammals and the fact that this enzyme is apparently essential for viral replication will suggest that NS5B polymerase is an ideal target for anti-HCV therapy. WO 00/06529 reports an inhibitor of NS5B, an α, γ-diketoic acid. WO 00/13708, WO 00/10573, WO 00/18231, and WO 01/47883 report NS5B inhibitors proposed for the treatment of HCV.

  Therefore, an object of the present invention is to provide a novel series of compounds with improved inhibitory activity against HCV polymerase.

In a first aspect of the invention, there are provided isomers, enantiomers, diastereoisomers, or tautomers of the compounds represented by Formula I, or salts thereof.

Where
A is O, S, NR ¹ or CR ¹ , wherein R ¹ is H, optionally halogen, OR ¹¹ , SR ¹¹ or N (R ¹² ) ₂ (wherein R ¹¹ and the respective R ¹² _Are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl-aryl or ( C _1-6 ) alkyl-Het, wherein said aryl or Het is optionally substituted with R ¹⁰ , or both R ¹² are covalently bonded together and they are both bonded Selected from the group consisting of (C _1-6 ) alkyl _optionally substituted with a 5-, 6- or 7-membered saturated heterocyclic ring.
----- represents a single bond or a double bond,
R ² is halogen, R ²¹ , OR ²¹ , SR ²¹ , COOR ²¹ , SO ₂ N (R ²² ) ₂ , N (R ²² ) ₂ , CON (R ²² ) ₂ , NR ²² C (O) R ²² or NR ²² C (O) NR ²² , wherein R ²¹ and each R ²² are independently H, (C _1-6 ) alkyl, haloalkyl, (C _2-6 ) alkenyl, (C _3-7 ) Cycloalkyl, (C _2-6 ) alkynyl, (C _5-7 ) cycloalkenyl, 6-membered or 10-membered aryl or Het, and R ²¹ and R ²² may be optionally substituted with R ²⁰ Or both R ²² are bonded together to form a 5-, 6- or 7-membered saturated heterocycle with the nitrogen to which they are attached;
B is NR ³ or CR ³ provided that one of A or B is CR ¹ or CR ³ , wherein R ³ is (C _1-6 ) alkyl, haloalkyl, (C _{3- 7} ) cycloalkyl, (C _5-7 ) cycloalkenyl, (C _6-10 ) bicycloalkyl, (C _6-10 ) bicycloalkenyl, 6- or 10-membered aryl, Het, (C _1-6 ) alkyl-aryl Or selected from (C _1-6 ) alkyl-Het,
Said alkyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, aryl, Het, alkyl-aryl and alkyl-Het are optionally halogen, or
a) if necessary
-OR ³¹ or SR ^{31 wherein} R ³¹ is H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 ) alkyl-aryl or (C _1-6 ) alkyl-Het), or
-N (R ³² ) _{2 wherein} each R ³² is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 ) alkyl-aryl or (C _1-6 ) alkyl-Het, or both R ³² are covalently bonded together and the nitrogen to which they are bonded To form a 5-, 6- or 7-membered saturated heterocyclic ring)
(C _1-6 ) alkyl _optionally substituted by
b) OR ^{33 wherein} R ³³ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het , (C _1-6 ) alkyl-aryl or (C _1-6 ) alkyl-Het),

c) SR ^{34 wherein} R ³⁴ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 ) alkyl-aryl or (C _1-6 ) alkyl-Het), and
d) N (R ³⁵ ) _{2 wherein} each R ³⁵ is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _{3- 7} ) Cycloalkyl, aryl, Het, (C _1-6 ) alkyl-aryl or (C _1-6 ) alkyl-Het, or both R ³⁵ are covalently bonded together and they are bonded Bonded to nitrogen to form a 5-, 6-, or 7-membered saturated heterocycle)
May be substituted with 1 to 4 substituents selected from
K is N or CR ⁴ , wherein R ⁴ is H, halogen, (C _1-6 ) alkyl, haloalkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _{3- 7} ) cycloalkyl, or R ⁴ is OR ⁴¹ or SR ⁴¹ , COR ⁴¹ or NR ⁴¹ COR ^{41 wherein} each R ⁴¹ is independently H, (C _1-6 ) alkyl, (C _3-7 ) Cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl), or R ⁴ is NR ⁴² R ^{43 where} R ⁴² and R ⁴³ are each independently H, ( C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, or both R ⁴² and R ⁴³ are covalently bonded together, And bonded to the nitrogen to which they are attached to form a 5-, 6-, or 7-membered saturated heterocycle),
L is N or CR ⁵ where R ⁵ has the same definition as R ⁴ defined above;
M is N or CR ⁷ where R ⁷ has the same definition as R ⁴ defined above;
Y ¹ is O or S;

Z is OR ⁶ where R ⁶ is
-OPO ₃ H, NO ₂ , cyano, azide, C (= NH) NH ₂ , C (= NH) NH (C _1-6 ) alkyl or C (= NH) NHCO (C _1-6 ) alkyl 1 to 4 substituents, or
a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, C _3-7 spirocycloalkyl optionally containing 1 or 2 heteroatoms, (C _2-6 ) Alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl (all of which may optionally be substituted with R ¹⁵⁰ ),
b) OR ¹⁰⁴ (where R ¹⁰⁴ is (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cyclo) substituted with R ¹⁵⁰ Alkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, said cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
c) OCOR ^{105 wherein} R ¹⁰⁵ is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het, the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is optionally R ¹⁵⁰ May be substituted),
d) SR ¹⁰⁸ , SO ₃ H, SO ₂ N (R ¹⁰⁸ ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ¹⁰⁸ (wherein each R ¹⁰⁸ is independently H, (C _1-6 ) In alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het Or both R ¹⁰⁸ are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6- or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het , (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het or a heterocyclic ring may be optionally substituted with R ¹⁵⁰ ),
e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ¹¹² is H, CN, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, COOR ¹¹⁵ or SO ₂ R ^{115 where} R ¹¹⁵ Is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or ( C _1-6 alkyl) Het), provided that when R ¹¹¹ is H or unsubstituted alkyl, provided that R ¹¹² is not H or unsubstituted alkyl, or R ¹¹¹ and R ¹¹² Both are covalently bonded together, and to the nitrogen to which they are bonded 5- is engaged, to form a 6-membered or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, or heterocycle Optionally substituted with R ¹⁵⁰ ),

f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) Alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- ( C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹¹⁸ is covalently bound to R ¹¹⁹ and they are bound Bonded to nitrogen to form a 5-, 6-, or 7-membered saturated heterocycle, or ^R119 and ^R120 are covalently bonded together and bonded to the nitrogen to which they are bonded, 5-membered, 6-membered Or a 7-membered saturated heterocycle, the alkyl, cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _{1- 6} alkyl) Het or heterocycle being optionally substituted with R ^0.99 if necessary),
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ and R ¹²² are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ), respectively. Cycloalkyl, 6- or 10-membered aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het is optionally substituted with R ¹⁵⁰ , or R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ , wherein R ¹²³ and each R ¹²⁴ is independently H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), or both R ¹²⁴ are covalently linked together to form a 5-membered, 6 Form a 7-membered or 7-membered saturated heterocyclic ring Kill, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het and heterocycle optionally substituted with R ¹⁵⁰ ),
i) COR ^{127 wherein} R ¹²⁷ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het , (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is necessary ^Optionally substituted by R ¹⁵⁰ )

j) COOR ^{128 wherein} R ¹²⁸ is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl substituted with R ¹⁵⁰ , Aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ¹²⁹ and R ¹³⁰ are covalently bonded together and they are bonded Combined with nitrogen to form a 5-, 6- or 7-membered saturated heterocycle, the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁵⁰ ),
l) Aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het (all of which may optionally be substituted with R ¹⁵⁰ )
C _1-6 alkyl substituted with 1 to 4 substituents selected from: R ¹⁵⁰ is
- halogen, NO _2, cyano, 1 to 3 substituents selected from azido, or
a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, C _3-7 spirocycloalkyl optionally containing 1 or 2 heteroatoms, (C _2-6 ) Alkenyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl (all of which may optionally be substituted with R ¹⁶⁰ ),

b) OR ^{104 wherein} R ¹⁰⁴ is H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, wherein the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is Optionally substituted with R ¹⁶⁰ ),
c) OCOR ^{105 wherein} R ¹⁰⁵ is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het, the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is optionally R ¹⁵⁰ May be substituted),
d) SR ¹⁰⁸ , SO ₂ N (R ¹⁰⁸ ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ¹⁰⁸ , wherein each R ¹⁰⁸ is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ^{108 of the above} are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6- or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het or heterocycle being optionally substituted with R ¹⁶⁰ as required),
e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het and R ¹¹² is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _{1- 6} ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, COOR ¹¹⁵ or SO ₂ R ^{115 where} R ¹¹⁵ is ( C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _{1 -6} alkyl) Het), or both R ¹¹¹ and R ¹¹² are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6-, or 7-membered saturated heterocycle. formed, said alkyl, cycloalkyl, aryl, Het, (C _1-6 Al Le) aryl or (C _1-6 alkyl) Het, or heterocycle being optionally substituted with R ¹⁶⁰ as required),
f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) Alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁶⁰ ),

g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- ( C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹¹⁹ and R ¹²⁰ are covalently bonded together and they are bonded To form a 5-membered, 6-membered or 7-membered saturated heterocyclic ring, and the alkyl, cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, ( C _1-6 alkyl) aryl or (C _1-6 alkyl) Het or heterocycle may be optionally substituted with R ¹⁶⁰ ),
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ is H, (C _1-6 ) alkyl optionally substituted with R ¹⁶⁰ , and R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ Wherein R ¹²³ and each R ¹²⁴ are independently H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cyclo Alkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), or both R ¹²⁴ are together To form a 5-membered, 6-membered or 7-membered saturated heterocyclic ring, and the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁶⁰ ),
j) Tetrazole, COOR ¹²⁸ (wherein R ¹²⁸ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl) , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁶⁰ ), and

k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ¹²⁹ and R ¹³⁰ are covalently bonded together and they are bonded Combined with nitrogen to form a 5-, 6- or 7-membered saturated heterocycle, the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁶⁰ ),
Selected from 1 to 3 substituents selected from
R ¹⁶⁰ is tetrazole, halogen, CN, C _1-6 alkyl, haloalkyl, COOR ¹⁶¹ , SO ₃ H, SO ₂ R ¹⁶¹ , OR ¹⁶¹ , N (R ¹⁶² ) ₂ , SO ₂ N (R ¹⁶² ) ₂ , NR ¹⁶² 1 or 2 substituents selected from COR ¹⁶² or CON (R ¹⁶² ) ₂ , wherein R ¹⁶¹ and each R ¹⁶² are independently H, (C _1-6 ) alkyl, ( C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, or both R ¹⁶² are covalently bonded together and bonded to the nitrogen to which they are bonded. Form a 5-membered, 6-membered or 7-membered saturated heterocyclic ring, or Z is OR ⁶ , wherein R ⁶ is
1 to 4 selected from -OPO ₃ H, azide, C (= NH) NH ₂ , C (= NH) NH (C _1-6 ) alkyl or C (= NH) NHCO (C _1-6 ) alkyl A substituent of
a) (C _1-6 ) alkyl, haloalkyl, (C _3-7 ) cycloalkyl substituted with R ^150a , C _3-7 spirocycloalkyl optionally containing 1 or 2 heteroatoms , (C _2-6 ) alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl (said haloalkyl, cycloalkyl, spirocycloalkyl, alkenyl, alkynyl and alkyl- Cycloalkyl may be optionally substituted with R ¹⁵⁰ , and R ^150a is COOR ^150b , N (R ^150b ) ₂ , NR ^150b C (O) R ^150b , OR ^150b , SR ^150b , SO ₂ R ^150b , SO ₂ N (R ^150b ) is the same as R ¹⁵⁰ except that it is not ₂ , and R ^150b is H or unsubstituted C _1-6 alkyl)
b) OR ¹⁰⁴ (where R ¹⁰⁴ is (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cyclo) substituted with R ¹⁵⁰ Alkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, said cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
c) OCOR ^{105 wherein} R ¹⁰⁵ is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het, the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is optionally R ¹⁵⁰ May be substituted),

d) SR ^108a , SO ₂ N (R ^108a ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ¹⁰⁸ , wherein each R ¹⁰⁸ is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ^{108 of the above} are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6- or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het or heterocycle may be optionally substituted with R ¹⁵⁰ and R ^108a is the same as R ¹⁰⁸ except that it is not H or unsubstituted C _1-6 alkyl ),
e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ¹¹² is H, CN, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, provided that R ¹¹¹ is H or unsubstituted alkyl In some cases, provided that R ¹¹² is not H or unsubstituted alkyl, or R ¹¹² is also COOR ¹¹⁵ or SO ₂ R ^{115a where} R ¹¹⁵ is H, (C _1-6 ) alkyl, ( C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ^115a, except not H or unsubstituted alkyl is the same as R ¹¹⁵ , And the or both by R ¹¹¹ and R ¹¹² are covalently bonded together, and 5-membered has been joined to the nitrogen to which they are attached form a 6-membered or 7-membered saturated heterocycle, said alkyl, cycloalkyl , Aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or a heterocycle may be optionally substituted with R ¹⁵⁰ ),

f) NR ¹¹⁶ COR ¹¹⁷ (wherein, R ¹¹⁶ and R ¹¹⁷ is substituted with each R ¹⁵⁰ (C _1-6) alkyl, (C _3-7) cycloalkyl, (C _1-6) alkyl - (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- ( C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- ( C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹¹⁸ is covalently bound to R ¹¹⁹ and they are bound Bonded to nitrogen to form a 5-, 6-, or 7-membered saturated heterocycle, or ^R119 and ^R120 are covalently bonded together, and bonded to the nitrogen to which they are bonded, 5-membered, 6-membered Or a 7-membered saturated heterocycle, the alkyl, cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _{1- 6} alkyl) Het or heterocycle being optionally substituted with R ^0.99 if necessary),
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ and R ¹²² are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ), respectively. Cycloalkyl, 6- or 10-membered aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het is optionally substituted with R ¹⁵⁰ , or R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ , wherein R ¹²³ and each R ¹²⁴ is independently H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), or both R ¹²⁴ are covalently bonded together to form a 5-membered, 6 Forming a 7-membered or 7-membered saturated heterocyclic ring, Alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het and heterocycle optionally substituted with R ¹⁵⁰ ),
i) COR ^{127 wherein} R ¹²⁷ is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl substituted with R ¹⁵⁰ , Aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, said cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het May be optionally substituted with R ¹⁵⁰ ),

j) COOR ^{128 wherein} R ¹²⁸ is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl substituted with R ¹⁵⁰ , Aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, provided that when R ¹²⁹ is H or unsubstituted alkyl, R ¹³⁰ is H or Provided that it is not a substituted alkyl, or both R ¹²⁹ and R ¹³⁰ are covalently bonded together and bonded to the nitrogen to which they are attached to form a 5-, 6- or 7-membered saturated heterocycle. , The alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het and heterocycle may be optionally substituted with R ¹⁵⁰ ),
l) Aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het (all of which may optionally be substituted with R ¹⁵⁰ )
R ¹⁵⁰ is (C _1-6 alkyl) aryl substituted with 1 to 4 substituents selected from
1 to 3 substituents selected from halogen, NO ₂ , cyano or azide, or
a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, C _3-7 spirocycloalkyl optionally containing 1 or 2 heteroatoms, (C _2-6 ) Alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl (all of which may optionally be substituted with R ¹⁶⁰ ),

b) OR ^{104 wherein} R ¹⁰⁴ is H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, wherein the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is Optionally substituted with R ¹⁶⁰ ),
c) OCOR ^{105 wherein} R ¹⁰⁵ is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het, the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is optionally R ¹⁵⁰ May be substituted),
d) SR ¹⁰⁸ , SO ₂ N (R ¹⁰⁸ ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ¹⁰⁸ , wherein each R ¹⁰⁸ is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ^{108 of the above} are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6- or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het or heterocycle being optionally substituted with R ¹⁶⁰ as required),
e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ¹¹² is H, CN, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, COOR ¹¹⁵ or SO ₂ R ^{115 where} R ¹¹⁵ Is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or ( C _1-6 alkyl) Het), or both R ¹¹¹ and R ¹¹² are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-membered, 6-membered or 7-membered saturated complex. Forming a ring, said alkyl, cycloalkyl, aryl, Het, (C _1-6 Alkyl) aryl or (C _1-6 alkyl) Het, or a heterocycle optionally substituted with R ¹⁶⁰ ),
f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) Alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁶⁰ ),

g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- ( C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹¹⁹ and R ¹²⁰ are covalently bonded together and they are bonded To form a 5-membered, 6-membered or 7-membered saturated heterocyclic ring, and the alkyl, cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, ( C _1-6 alkyl) aryl or (C _1-6 alkyl) Het or heterocycle may be optionally substituted with R ¹⁶⁰ ),
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ is H, (C _1-6 ) alkyl optionally substituted with R ¹⁶⁰ , and R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ Wherein R ¹²³ and each R ¹²⁴ are independently H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cyclo Alkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), or both R ¹²⁴ are together To form a 5-membered, 6-membered or 7-membered saturated heterocyclic ring, and the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁶⁰ ),
j) Tetrazole, COOR ¹²⁸ (wherein R ¹²⁸ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl) , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁶⁰ ), and

k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ¹²⁹ and R ¹³⁰ are covalently bonded together and they are bonded Combined with nitrogen to form a 5-, 6- or 7-membered saturated heterocycle, the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁶⁰ ),
1 to 3 substituents selected from
R ¹⁶⁰ is tetrazole, halogen, CN, C _1-6 alkyl, haloalkyl, COOR ¹⁶¹ , SO ₃ H, SO ₂ R ¹⁶¹ , OR ¹⁶¹ , N (R ¹⁶² ) ₂ , SO ₂ N (R ¹⁶² ) ₂ , NR ¹⁶² Defined as one or two substituents selected from COR ¹⁶² or CON (R ¹⁶² ) ₂ , wherein R ¹⁶¹ and R ¹⁶² are as defined above, or Z is OR ⁶ (formula R ⁶ is (C _3-6 ) cycloalkyl, (C _2-6 ) alkenyl, 6-membered or 10-membered aryl, Het, (C _1-6 ) alkyl-Het, and the cycloalkyl, alkenyl, aryl , Het or alkyl-Het is optionally substituted with R ⁶⁰ ), or Z is N (R ^6a ) R ⁶ , wherein R ^6a is H or (C _1-6 alkyl) And
R ⁶ as required
-OPO ₃ H, NO ₂ , cyano, azide, C (= NH) NH ₂ , C (= NH) NH (C _1-6 ) alkyl or C (= NH) NHCO (C _1-6 ) alkyl 1 to 4 substituents, or
a) (C _1-6 ) alkyl substituted with R ^150a , haloalkyl substituted with R ¹⁵⁰ , (C _3-7 ) cycloalkyl, optionally containing 1 or 2 heteroatoms _3-7 spirocycloalkyl, (C _2-6 ) alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl (all of which are optionally substituted with R ¹⁵⁰ R ^150a may be halogen, OH, O (C _1-6 alkyl), COOH, COO (C _1-6 alkyl), NH ₂ , NH (C _1-6 alkyl) and N (C _1- alkyl). ₆ alkyl) same as R ¹⁵⁰ except not ₂ ),
b) OR ¹⁰⁴ (where R ¹⁰⁴ is (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cyclo) substituted with R ¹⁵⁰ Alkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, said cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),

c) OCOR ^{105 wherein} R ¹⁰⁵ is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het, the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is optionally R ¹⁵⁰ May be substituted),
d) SR ¹⁰⁸ , SO ₃ H, SO ₂ N (R ¹⁰⁸ ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ¹⁰⁸ (wherein each R ¹⁰⁸ is independently H, (C _1-6 ) In alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het Or both R ¹⁰⁸ are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6- or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het , (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het or a heterocyclic ring may be optionally substituted with R ¹⁵⁰ ),
e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ¹¹² is H, CN, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, COOR ¹¹⁵ or SO ₂ R ^{115 where} R ¹¹⁵ Is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or ( C _1-6 alkyl) Het), provided that when R ¹¹¹ is H or unsubstituted alkyl, provided that R ¹¹² is not H or unsubstituted alkyl, or R ¹¹¹ and R ¹¹² Both are covalently bonded together, and to the nitrogen to which they are bonded 5- is engaged, to form a 6-membered or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or heterocycle Optionally substituted with R ¹⁵⁰ ),

f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) Alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- ( C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹¹⁸ is covalently bound to R ¹¹⁹ and they are bound Bonded to nitrogen to form a 5-, 6-, or 7-membered saturated heterocycle, or ^R119 and ^R120 are covalently bonded together, and bonded to the nitrogen to which they are bonded, 5-membered, 6-membered Or a 7-membered saturated heterocycle, the alkyl, cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _{1- 6} alkyl) Het or heterocycle being optionally substituted with R ^0.99 if necessary),
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ and R ¹²² are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ), respectively. Cycloalkyl, 6- or 10-membered aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het is optionally substituted with R ¹⁵⁰ , or R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ , wherein R ¹²³ and each R ¹²⁴ is independently H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), or both R ¹²⁴ are covalently linked together to form a 5-membered, 6 Form a 7-membered or 7-membered saturated heterocyclic ring Kill, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het and heterocycle optionally substituted with R ¹⁵⁰ ),

i) COR ^{127 wherein} R ¹²⁷ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het , (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is necessary ^Optionally substituted by R ¹⁵⁰ )
j) COOR ^{128 wherein} R ¹²⁸ is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl substituted with R ¹⁵⁰ , Aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ¹²⁹ and R ¹³⁰ are covalently bonded together and they are bonded Combined with nitrogen to form a 5-, 6- or 7-membered saturated heterocycle, the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁵⁰ ),
l) Aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het (all of which may optionally be substituted with R ¹⁵⁰ )
(C _1-6 ) alkyl _optionally substituted with 1 to 4 substituents selected from R ¹⁵⁰
- halogen, NO _2, cyano, 1 to 3 substituents selected from azido, or

a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, C _3-7 spirocycloalkyl optionally containing 1 or 2 heteroatoms, (C _2-6 ) Alkenyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl (all of which may optionally be substituted with R ¹⁶⁰ ),
b) OR ^{104 wherein} R ¹⁰⁴ is H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, wherein the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is Optionally substituted with R ¹⁶⁰ ),
c) OCOR ^{105 wherein} R ¹⁰⁵ is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het, the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is optionally in R ¹⁶⁰ May be substituted),
d) SR ¹⁰⁸ , SO ₂ N (R ¹⁰⁸ ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ¹⁰⁸ , wherein each R ¹⁰⁸ is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ^{108 of the above} are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6- or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het or heterocycle being optionally substituted with R ¹⁶⁰ as required),
e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het and R ¹¹² is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _{1- 6} ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, COOR ¹¹⁵ or SO ₂ R ^{115 where} R ¹¹⁵ is ( C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _{1 -6} alkyl) Het), or both R ¹¹¹ and R ¹¹² are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6-, or 7-membered saturated heterocycle. formed, said alkyl, cycloalkyl, aryl, Het, (C _1-6 Al Le) aryl or (C _1-6 alkyl) Het, or heterocycle being optionally substituted with R ¹⁶⁰ as required),

f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) Alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁶⁰ ),
g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- ( C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹¹⁹ and R ¹²⁰ are covalently bonded together and they are bonded To form a 5-membered, 6-membered or 7-membered saturated heterocyclic ring, and the alkyl, cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, ( C _1-6 alkyl) aryl or (C _1-6 alkyl) Het or heterocycle may be optionally substituted with R ¹⁶⁰ ),
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ is H, (C _1-6 ) alkyl optionally substituted with R ¹⁶⁰ , and R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ Wherein R ¹²³ and each R ¹²⁴ are independently H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cyclo Alkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), or both R ¹²⁴ are together To form a 5-membered, 6-membered or 7-membered saturated heterocyclic ring, and the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁶⁰ ),

j) Tetrazole, COOR ¹²⁸ (wherein R ¹²⁸ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl) , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁶⁰ ), and
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ¹²⁹ and R ¹³⁰ are covalently bonded together and they are bonded Combined with nitrogen to form a 5-, 6- or 7-membered saturated heterocycle, the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁶⁰ ),
Selected from 1 to 3 substituents selected from
R ¹⁶⁰ is tetrazole, halogen, CN, C _1-6 alkyl, haloalkyl, COOR ¹⁶¹ , SO ₃ H, SO ₂ R ¹⁶¹ , OR ¹⁶¹ , N (R ¹⁶² ) ₂ , SO ₂ N (R ¹⁶² ) ₂ , NR ¹⁶² Defined as one or two substituents selected from COR ¹⁶² or CON (R ¹⁶² ) ₂ , wherein R ¹⁶¹ and R ¹⁶² are as defined above, or Z is N (R ^6a ) R ⁶ wherein R ^6a is as defined above and R ⁶ is (C _3-6 ) cycloalkyl, (C _2-6 ) alkenyl, 6- or 10-membered aryl, Het , (C _1-6 ) alkyl-aryl, (C _1-6 ) alkyl-Het, wherein said alkyl, cycloalkyl, alkenyl, aryl, Het, alkyl-aryl, or alkyl-Het are all optionally R ⁶⁰ Optionally substituted, or Z is OR ⁶ or N (R ^6a ) R ⁶ , wherein R ^6a is as defined above, and R ⁶ is

And
In which R ⁷ and R ⁸ are each independently H, (C _1-6 ) alkyl, haloalkyl, (C _3-7 ) cycloalkyl, 6- or 10-membered aryl, Het, (C _1-6 ) alkyl- Aryl, (C _1-6 ) alkyl-Het, the alkyl, cycloalkyl, aryl, Het, (C _1-6 ) alkyl-aryl, (C _1-6 ) alkyl-Het optionally substituted with R ⁷⁰ May have been, or
R ⁷ and R ⁸ are covalently bonded together to form a 4-membered, 5- or 6-membered (C _3-7 ) cycloalkyl or 1 to 3 heteroatoms selected from O, N, and S Forms a membered heterocyclic ring, or when Z is N (R ^6a ) R ⁶ , either R ⁷ or R ⁸ is covalently bonded to R ^6a to form a nitrogen-containing five-membered or six-membered heterocyclic ring And
Y ² is O or S;
R ⁹ is H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 ) alkyl -Aryl or (C _1-6 ) alkyl-Het, all of which may optionally be substituted with R ⁹⁰ , or
R ⁹ is covalently bonded to either R ⁷ or R ⁸ to form a 5 or 6 membered heterocyclic ring,
Q is 6- or 10-membered aryl, Het, (C _1-6 ) alkyl-aryl, (C _1-6 ) alkyl-Het, (C _1-6 ) alkyl-CONH-aryl or (C _1-6 ) alkyl -CONH-Het, all of these are needed

Or may be substituted with a salt or derivative thereof,
Het is a 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N, and S, or a 9-membered having 1 to 5 heteroatoms selected from O, N, and S Or defined as a 10-membered heterocycle,
R ¹⁰ , R ²⁰ , R ⁶⁰ , R ⁷⁰ , R ⁹⁰ and R ¹⁰⁰ are each
-From halogen, OPO ₃ H, NO ₂ , cyano, azide, C (= NH) NH ₂ , C (= NH) NH (C _1-6 ) alkyl or C (= NH) NHCO (C _1-6 ) alkyl 1 to 4 selected substituents, or
a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, C _3-7 spirocycloalkyl optionally containing 1 or 2 heteroatoms, (C _2-6 ) Alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl (all of which may optionally be substituted with R ¹⁵⁰ ),
b) OR ^{104 wherein} R ¹⁰⁴ is H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, wherein the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is Optionally substituted with R ¹⁵⁰ ),
c) OCOR ^{105 wherein} R ¹⁰⁵ is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het, the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is optionally R ¹⁵⁰ May be substituted),
d) SR ¹⁰⁸ , SO ₂ N (R ¹⁰⁸ ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ¹⁰⁸ , wherein each R ¹⁰⁸ is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ^{108 of the above} are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6- or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het or heterocycle may be optionally substituted with R ¹⁵⁰ ),

e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ¹¹² is H, CN, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, COOR ¹¹⁵ or SO ₂ R ^{115 where} R ¹¹⁵ Is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or ( C _1-6 alkyl) Het), or both R ¹¹¹ and R ¹¹² are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-membered, 6-membered or 7-membered saturated complex. Forming a ring, said alkyl, cycloalkyl, aryl, Het, (C _1-6 Alkyl) aryl or (C _1-6 alkyl) Het, or a heterocycle optionally substituted with R ¹⁵⁰ ),
f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) Alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- ( C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹¹⁸ is covalently bound to R ¹¹⁹ and they are bound Bonded to nitrogen to form a 5-, 6-, or 7-membered saturated heterocycle, or ^R119 and ^R120 are covalently bonded together, and bonded to the nitrogen to which they are bonded, 5-membered, 6-membered Or a 7-membered saturated heterocycle, the alkyl, cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _{1- 6} alkyl) Het or heterocycle being optionally substituted with R ^0.99 if necessary),

h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ and R ¹²² are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ), respectively. Cycloalkyl, 6- or 10-membered aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het is optionally substituted with R ¹⁵⁰ , or R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ , wherein R ¹²³ and each R ¹²⁴ is independently H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), or both R ¹²⁴ are covalently bonded together to form a 5-membered, 6 Forming a 7-membered or 7-membered saturated heterocyclic ring, Alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het and heterocycle optionally substituted with R ¹⁵⁰ ),
i) COR ^{127 wherein} R ¹²⁷ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het , (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is necessary ^Optionally substituted by R ¹⁵⁰ )
j) COOR ^{128 wherein} R ¹²⁸ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het , (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ¹²⁹ and R ¹³⁰ are covalently bonded together and they are bonded Combined with nitrogen to form a 5-, 6- or 7-membered saturated heterocycle, the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁵⁰ ),
l) Aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het (all of which may optionally be substituted with R ¹⁵⁰ )
And R ¹⁵⁰ is defined as 1 to 4 substituents selected from
-From halogen, OPO ₃ H, NO ₂ , cyano, azide, C (= NH) NH ₂ , C (= NH) NH (C _1-6 ) alkyl or C (= NH) NHCO (C _1-6 ) alkyl 1 to 3 selected substituents, or
a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, C _3-7 spirocycloalkyl optionally containing 1 or 2 heteroatoms, (C _2-6 ) Alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl (all of which may optionally be substituted with R ¹⁶⁰ ),

b) OR ^{104 wherein} R ¹⁰⁴ is H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, wherein the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is Optionally substituted with R ¹⁶⁰ ),
c) OCOR ^{105 wherein} R ¹⁰⁵ is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het, the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is optionally in R ¹⁶⁰ May be substituted),
d) SR ¹⁰⁸ , SO ₂ N (R ¹⁰⁸ ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ¹⁰⁸ , wherein each R ¹⁰⁸ is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ^{108 of the above} are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6- or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het or heterocycle being optionally substituted with R ¹⁶⁰ as required),

e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ¹¹² is H, CN, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, COOR ¹¹⁵ or SO ₂ R ^{115 where} R ¹¹⁵ Is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or ( C _1-6 alkyl) Het), or both R ¹¹¹ and R ¹¹² are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-membered, 6-membered or 7-membered saturated complex. Forming a ring, said alkyl, cycloalkyl, aryl, Het, (C _1-6 Alkyl) aryl or (C _1-6 alkyl) Het, or a heterocycle optionally substituted with R ¹⁶⁰ ),
f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) Alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁶⁰ ),
g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- ( C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹¹⁸ is covalently bound to R ¹¹⁹ and they are bound Bonded to nitrogen to form a 5-, 6-, or 7-membered saturated heterocycle, or R ¹¹⁸ and R ¹²⁰ are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6-membered Or a 7-membered saturated heterocycle, the alkyl, cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _{1- 6} alkyl) Het or heterocycle being optionally substituted with R ¹⁶⁰ as required),
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ and R ¹²² are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ), respectively. Cycloalkyl, 6- or 10-membered aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het is optionally substituted with R ¹⁶⁰ , or R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ , wherein R ¹²³ and each R ¹²⁴ is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), or both R ¹²⁴ are covalently bonded together to form a 5-membered, 6 Forming a 7-membered or 7-membered saturated heterocycle, Alkyl, cycloalkyl, alkyl - cycloalkyl, aryl, Het, optionally substituted with (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het and R ¹⁶⁰ by heterocycle necessary),

i) COR ¹²⁷ (wherein R ¹²⁷ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, wherein the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is Optionally substituted with R ¹⁶⁰ ),
j) Tetrazole, COOR ¹²⁸ (wherein R ¹²⁸ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl) , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁶⁰ ), and

k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ¹²⁹ and R ¹³⁰ are covalently bonded together and they are bonded Combined with nitrogen to form a 5-, 6- or 7-membered saturated heterocycle, the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁶⁰ ),
Defined as 1 to 3 substituents selected from
R ¹⁶⁰ is tetrazole, halogen, CN, C _1-6 alkyl, haloalkyl, COOR ¹⁶¹ , SO ₃ H, SR ¹⁶¹ , SO ₂ R ¹⁶¹ , OR ¹⁶¹ , N (R ¹⁶² ) ₂ , SO ₂ N (R ¹⁶² ) ₂ , NR ¹⁶² COR ¹⁶² or CON (R ¹⁶² ) ₂ defined as one or two substituents, wherein R ¹⁶¹ and each R ¹⁶² are independently H, (C _1-6 ) alkyl , (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, or both R ¹⁶² are covalently bonded together and the nitrogen to which they are bonded To form a 5-membered, 6-membered or 7-membered saturated heterocyclic ring,
Provided that A is CH, R ² is phenyl or N-butyl, B is NR ³ , R ³ is Me, K is CH, L is CH, and M is CH , Y ¹ is O and Z is NHR ⁶ , R ⁶ is

It is a condition that it is not.
Also in a first aspect of the invention, the formula Ia:

Or a salt thereof is provided.
Where
A is O, S, NR ¹ , or CR ¹ ;
B is NR ³ or CR ³
R ¹ has ¹ to 4 heteroatoms selected from H, (C _1-6 ) alkyl, benzyl, (C _1-6 alkyl)-(C _6-10 aryl), O, N, and S Selected from the group consisting of (C _1-6 alkyl) -5-membered or 6-membered heterocycle and 5-membered or 6-membered heterocycle having 1-4 heteroatoms selected from O, N and S;
The benzyl and the heteroatom may be optionally substituted with 1 to 4 substituents selected from the group consisting of COOH, COO (C _1-6 alkyl), halogen, and (C _1-6 alkyl). Often,
R ² is 5-membered or 6-membered having 1 to 4 heteroatoms selected from H, halogen, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, phenyl, O, N, and S Selected from the group consisting of heterocycles, pyridine-N-oxides, and 9- or 10-membered bicyclic heterocycles having 1 to 4 heteroatoms selected from O, N and S;
The phenyl, heterocycle and bicyclic heterocycle are optionally halogen, C (halogen) ₃ , (C _1-6 ) alkyl, OH, O (C _1-6 alkyl), NH ₂ , and N (C _{1- (6} alkyl) optionally substituted with 1 to 4 substituents selected from the group consisting of ₂ ;
R ³ is a 5-, 6- or 7-membered heterocycle having 1 to 4 heteroatoms selected from O, N, and S, norbornane, (C _3-7 ) cycloalkyl and (C _3-7 ) Selected from the group consisting of cycloalkyl- (C _1-6 alkyl);
M is N, CR ⁴ , or COR ⁵ , wherein R ⁴ is selected from the group consisting of H, halogen, and (C _1-6 alkyl), and R ⁵ is H and (C _1-6 alkyl) )
K and L are N or CH,
----- represents a single bond or a double bond,

Y is O or S;
Z is OR ⁶ or NR ⁶ R ^6a ;
R ⁶ is H, (C _1-6 ) alkyl, (C _3-6 ) cycloalkyl, (C _3-6 ) cycloalkyl (C _1-6 ) alkyl, (C _6-10 ) aryl, (C _{6- 10} ) aryl (C _1-6 ) alkyl, (C _2-6 ) alkenyl, (C _3-6 ) cycloalkyl (C _2-6 ) alkenyl, (C _6-10 ) aryl (C _2-6 ) alkenyl, 1-4 selected from N {(C _1-6 ) alkyl} ₂ , NHCOO (C _1-6 ) alkyl (C _6-10 ) aryl, NHCO (C _6-10 ) aryl, O, N and S A (C _1-6 ) alkyl-5 or 6 atom heterocycle having 5 heteroatoms and a 9 or 10 atom bicyclic heterocycle having 1 to 4 heteroatoms selected from O, N and S Selected from the group
The alkyl, cycloalkyl, aryl, alkenyl, and heterocyclic rings are all OH, COOH, COO (C _1-6 ) alkyl, (C _1-6 ) alkyl, (C _1-6 ) alkyl-hydroxy, phenyl, benzyl as necessary. 5-membered having 1 to 4 heteroatoms selected from oxy, halogen, (C _2-4 ) alkenyl, (C _2-4 ) alkenyl- (C _1-6 ) alkyl-COOH, O, N and S Or a 6-membered heterocycle (the above alkyl, cycloalkyl, aryl, alkenyl and heterocycle are (C _1-6 alkyl) if necessary, CF ₃ , OH, COOH, NHC (C _1-6 alkyl) ₂ , NHCO (C _{1 -6} alkyl), NH ₂ , NH (C _1-6 alkyl), and N (C _1-6 alkyl) ₂ optionally substituted with 1 to 4 substituents),
9-membered or 10-membered bicyclic heterocycle having 1 to 4 heteroatoms selected from O, N and S (the bicyclic heterocycle is optionally halogen, OPO ₃ H, sulfonamide, SO ₃ H _{, SO 2 CH 3, -CONH 2} , -COCH 3, (C 1-3) alkyl, (C _2-4 alkenyl) COOH, tetrazolyl, COOH, -CONH _{2, triazolyl, OH, NO 2, NH 2} , - O (C _1-6 alkyl) COOH, hydantoin, benzoylene urea, (C _1-4 ) alkoxy, cyano, azide, -O- (C _1-6 ) alkyl COOH, -O- (C _1-6 ) alkyl COO -(C _1-6 ) alkyl, NHCO (C _1-6 alkyl), -NHCOCOOH, -NHCOCONHOH, -NHCOCONH ₂ , -NHCOCONHCH ₃ , -NHCO (C _1-6 ) alkyl-COOH, -NHCOCONH (C _{1- 6} ) alkyl-COOH, -NHCO (C _3-7 ) cycloalkyl-COOH, -NHCONH (C _6-10 ) aryl-COOH, -NHCONH (C _6-10 ) aryl-COO (C _1-6 ) alkyl, -NHCONH (C _1-6 ) alkyl-COOH, -NHCONH (C _1-6 ) alkyl-COO (C _1-6 ) alkyl, -NHCONH (C _1-6 ) alkyl- (C _2-6 ) Alkenyl-COOH, -NH (C _1-6 ) alkyl- (C _6-10 ) aryl-O (C _1-6 ) alkylCOOH, -NH (C _1-6 ) alkyl- (C _6-10 ) aryl -COOH, -NHCH ₂ COOH, -NHCONH ₂ , -NHCO (C _1-6 ) hydroxyalkyl COOH, -OCO (C _1-6 ) hydroxyalkyl COOH, (C _3-6 ) cycloalkyl COOH

Optionally substituted with 1 to 4 substituents selected from —NHCN, —NHCHO, —NHSO ₂ CH ₃ , and —NHSO ₂ CF ₃ ),
Halogen, OPO ₃ H, sulfonamide, SO ₃ H, SO ₂ CH ₃ , -CONH ₂ , -COCH ₃ , (C _1-3 ) alkyl, (C _2-4 alkenyl) COOH, tetrazolyl, COOH,-if necessary CONH _{2, triazolyl, OH, NO 2, NH 2} , -O (C 1-6 alkyl) COOH, hydantoin, Benzoiren urea, (C _1-4) alkoxy, cyano, azido, -O- (C _1-6) Alkyl COOH, -O- (C _1-6 ) alkyl COO- (C _1-6 ) alkyl, NHCO (C _1-6 alkyl), -NHCOCOOH, -NHCOCONHOH, -NHCOCONH ₂ , -NHCOCONHCH ₃ , -NHCO (C _1-6 ) alkyl-COOH, -NHCOCONH (C _1-6 ) alkyl-COOH, -NHCO (C _3-7 ) cycloalkyl-COOH, -NHCONH (C _6-10 ) aryl-COOH, -NHCONH (C _{6 -10} ) aryl-COO (C _1-6 ) alkyl, -NHCONH (C _1-6 ) alkyl-COOH, -NHCONH (C _1-6 ) alkyl-COO (C _1-6 ) alkyl, -NHCONH (C _{1 -6} ) alkyl- (C _2-6 ) alkenyl-COOH, -NH (C _1-6 ) alkyl- (C _6-10 ) aryl-O (C _1-6 ) alkyl COOH, -NH (C _1-6 ) alkyl - (C _6-10) Ally _{-COOH, -NHCH 2 COOH, -NHCONH 2} , -NHCO (C 1-6) hydroxyalkyl COOH, -OCO (C _1-6) hydroxyalkyl COOH, (C _3-6) cycloalkyl COOH

6- or 10-membered aryl optionally substituted with 1 to 4 substituents selected from -NHCN, -NHCHO, -NHSO ₂ CH ₃ , and -NHSO ₂ CF ₃ ;
Coumarin, (C _1-6 ) alkyl-amino, NH (C _1-6 alkyl), C (halogen) ₃ , —NH (C _2-4 ) acyl, —NH (C _6-10 ) aroyl, —O ( C _1-6 alkyl) -Het may be substituted with 1 to 4 substituents selected from
R ^6a is covalently bonded to either H or either R ⁷ or R ⁸ to form a pyrrolidine (C _1-6 alkyl), or Z is

And
Where
W is CR ⁷ R ⁸ , and R ⁷ and R ⁸ are each independently H, (C _1-6 alkyl), (C _3-7 cycloalkyl), (C _1-6 alkyl) phenyl, (C _{1- 6} alkyl)-(C _3-7 cycloalkyl), (C _3-7 cycloalkyl)-(C _1-6 alkyl), (C _3-7 cycloalkyl)-(C _2-4 alkenyl), (C _{1 -6} alkyl) -OH, selected phenyl, CH ₂ biphenyl, O, N, and 5-membered or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from S, O, N, and S (C _1-6 alkyl) -5 member having 1 to 4 heteroatoms selected from 9-membered or 10-membered bicyclic heterocycle having 1 to 4 heteroatoms, O, N and S A 6-membered heterocycle or a (C _1-6 alkyl) -9-membered or 10-membered bicyclic heterocycle having 1 to 4 heteroatoms selected from O, N and S, or
R ⁷ and R ⁸ are covalently bonded together (C _3-7 cycloalkyl) and have a 4-, 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N, and S Form or
One of R ⁷ or R ⁸ is covalently bonded to R ⁹ to form pyrrolidine;
The alkyl, cycloalkyl, heterocycle, bicyclic heterocycle, and phenyl are OH, COOH, (C _1-6 alkyl), (C _2-4 alkenyl), CONH ₂ , NH ₂ , NH (C _{1- 6} alkyl), N (C _1-6 alkyl) ₂ , NHCOCOOH, NHCOCON (C _1-6 alkyl) ₂ , NHCOCONH (C _1-6 alkyl), SH, S (C _1-6 alkyl), NHC (= NH ) May be substituted with 1 to 4 substituents selected from the group consisting of NH ₂ , halogen, and COO (C _1-6 alkyl);
R ⁹ is H or (C _1-6 alkyl) and Q is selected from (C _1-3 alkyl) CONH aryl, 6-membered, 9-membered or 10-membered aryl, biphenyl, O, N, and S A 5- or 6-atom heterocycle having 1 to 4 heteroatoms, a 9- or 10-membered bicyclic heterocycle having 1 to 4 heteroatoms selected from O, N, and S;
(The aryl, biphenyl, heterocycle and bicyclic heterocycle are all OH, COOH, COO (C _1-6 ) alkyl, (C _1-6 ) alkyl, (C _1-6 ) alkyl COOH, (C _1-6 alkyl) (C _2-4 alkynyl), (C _1-6 ) alkyl-hydroxy, phenyl, benzyloxy, halogen, (C _2-4 ) alkenyl, (C _2-4 ) alkenyl- (C _{1- 6} ) 5 or 6 membered second heterocycle having 1 to 4 heteroatoms selected from alkyl-COOH, O, N and S, 1 to 4 selected from O, N and S May be substituted with 1 to 4 substituents selected from NH-5-membered or 6-membered second heterocycle having a heteroatom,
The second heterocyclic ring and phenyl are optionally (C _1-6 alkyl), CF ₃ , OH, (C _1-6 alkyl) COOH, O (C _1-6 alkyl) COOH, (C _1-6 alkyl) COO. (C _1-6 alkyl), CH ₂ phenyl, COO (C _1-6 alkyl), (C _1-6 alkyl) O (C _1-6 alkyl), COOH, NCH (C _1-6 alkyl) ₂ , NCO (C _1-6 alkyl), NH ₂ , NH (C _1-6 alkyl), halogen, and optionally substituted with 1 to 4 substituents selected from N (C _1-6 alkyl) ₂ ),
Halogen, OPO ₃ H, benzyl, sulfonamide, SH, SOCH ₃ , SO ₃ H, SO ₂ CH ₃ , S (C _1-6 alkyl) COOH, —CONH ₂ , —COCH ₃ , (C _1-3 ) alkyl , (C _2-4 alkenyl) COOH
(The alkenyl may be optionally substituted with 1 to 2 (C _1-6 alkyl) substituents),

(C _2-4 alkenyl) COO (C _1-6 alkyl), tetrazolyl, COOH, triazolyl, OH, NO ₂ , NH ₂ , -O (C _1-6 alkyl) COOH, hydantoin, benzoylene urea, (C _{1- 4} ) Alkoxy, (C _1-4 ) alkoxy (C _1-6 alkyl) COOH, cyano, azide, -O- (C _1-6 ) alkyl COOH, -O- (C _1-6 ) alkyl COO- (C _{1-6) alkyl, -NHCOCOOH, -NHCOCONHOH, -NHCOCONH 2,} -NHCOCONHCH 3, -NHCO (C 1-6) alkyl -COOH, -NHCOCONH (C _1-6) alkyl -COOH, -NHCO (C _{3- 7)} cycloalkyl -COOH, -NHCONH (C _6-10) aryl -COOH, -NHCONH (C _6-10) aryl -COO (C _1-6) alkyl, -NHCONH (C _1-6) alkyl -COOH, -NHCONH (C _1-6 ) alkyl-COO (C _1-6 ) alkyl, -NHCONH (C _1-6 ) alkyl- (C _2-6 ) alkenyl-COOH, -NH (C _1-6 ) alkyl- ( C _6-10 ) aryl-O (C _1-6 ) alkyl COOH, -NH (C _1-6 ) alkyl- (C _6-10 ) aryl-COOH, -NHCH ₂ COOH, -NHCONH ₂ , -NHCO (C _1-6) hydroxyalkyl COOH, -OCO (C _1-6) human Rokishiarukiru COOH, (C _3-6) cycloalkyl COOH,

-NHCN, -NHCHO, -NHSO ₂ CH ₃ , -NHSO ₂ CF ₃ , coumarin, (C _1-6 ) alkyl-amino, NH (C _1-6 alkyl) ₂ , C (halogen) ₃ , -NH (C _2-4) acyl, -NH (C _6-10) aroyl, -CONH (C _1-6 alkyl), - CO (C _1-6) alkyl -COOH, -CONH (C _1-6) alkyl -COOH, -CO-NH-alanyl, -CONH (C _2-4 ) alkyl N (C _1-6 alkyl) ₂ , -CONH (C _2-4 ) alkyl-Het, -CONH (C _2-4 ) alkyl- (COOH ) -Het, -CONH (C _1-2 alkyl) (OH) (C _1-2 alkyl) OH, -CONH (C _1-6 ) alkyl-COOH, -CONH (C _6-10 aryl), -CONH- Het, -CONH (C _6-10 ) aryl-COOH, -CONH (C _6-10 ) aryl-COO (C _1-6 ) alkyl, -CONH (C _1-6 ) alkyl-COO (C _1-6 ) It is selected from the group consisting of alkyl, —CONH (C _6-10 ) aryl- (C _1-6 ) alkyl-COOH, and —CONH (C _6-10 ) aryl- (C _2-6 ) alkenyl-COOH.
In a third aspect of the invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt thereof, as an inhibitor of the RNA-dependent RNA polymerase activity of the enzyme NS5B encoded by HCV.
In a fourth aspect of the invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt thereof, as an inhibitor of HCV replication.
In a fifth aspect of the present invention, there is provided a method of treating or preventing HCV infection in mammals, which comprises administering to the mammal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
In a sixth aspect of the invention, a pharmaceutical composition for the treatment or prevention of HCV infection, comprising an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Things are provided.
According to a particular embodiment, the pharmaceutical composition of the invention comprises an additional immunomodulator. Additional immunomodulators include, but are not limited to, α-, β-, δ-, γ-, and ω-interferon.
According to another embodiment, the pharmaceutical composition of the present invention may further comprise an antiviral agent. Examples of antiviral agents include ribavirin and amantadine.
According to another embodiment, the pharmaceutical composition of the invention may further comprise another inhibitor of HCV protease.
According to yet another embodiment, the pharmaceutical composition of the present invention may further comprise an inhibitor of other targets in the HCV life cycle, such as helicase, polymerase, metalloprotease or IRES.
In a seventh aspect of the invention, there is provided the use of a compound of formula I for the manufacture of a medicament for the treatment of HCV infection.
In an eighth aspect of the invention there is provided the use of a compound of formula I for preventing HCV infection.
In a ninth aspect of the invention there is provided the use of a compound of formula I as an HCV polymerase inhibitor.
In a tenth aspect of the present invention, the formula (1a) or (1b):

Wherein A, B, K, L, and M are as described herein and PG is H or a carboxy protecting group.
Intermediates are provided.
In an eleventh aspect of the present invention, the formula (iii)

Wherein A, R ² , B, K, L, M, and PG are as described herein.
A method for producing the compound of
a) In the presence of a metal catalyst (eg Pd, Ni, Ru, Cu), a base and an additive (eg phosphine ligand, Cu salt, Li salt, ammonium salt, CsF) in a suitable solvent, the intermediate ( 1a)

R ² -X wherein R ¹ , R ² , K, L, M and PG are as described herein, and X is Sn (C _1-6 alkyl) ₃ , Sn (aryl ) ₃ , metal halide, B (OH) ₂ , and B (O (C _1-6 ) alkyl) ₂ , but not limited to, to form a compound of formula (iii) The manufacturing method is provided.
In another method of the eleventh aspect of the present invention, the formula (iii)

Wherein A, R ² , B, K, L, M, and PG are as described herein.
A method for producing the compound of
b) In the presence of a metal catalyst (eg Pd, Ni, Ru, Cu), a base and an additive (eg phosphine ligand, Cu salt, Li salt, ammonium salt, CsF) in a suitable solvent, the intermediate ( 1b)

R ² -X ′ (wherein X ′ is a halide, OSO ₂ (C _1-6 alkyl), OSO ₂ Ar, OSO ₂ CF _3, etc.) and M is a metal such as Li, Sn (C _1-6 alkyl) ₃ , Sn (aryl) ₃ , B (OH) ₂ , B (O (C _1-6 ) alkyl) ₂ , which is a metal halide) to give a compound of formula (iii) The manufacturing method is provided.
In a thirteenth aspect of the invention, Formula 1c:

Wherein A, R ² , B, K, L, M, R ⁷ and R ⁸ are as described herein.
An intermediate compound represented by: or a salt or derivative thereof is provided.
In the fourteenth aspect of the present invention,
a) a coupling agent in a mixture with or without an aprotic solvent at a temperature of about 20 ° C. to about 170 ° C., and intermediate 1c:

Is coupled with an amine Q-NH ₂ to form a compound of formula I wherein A, R ² , B, R ⁷ , R ⁸ , Q, K, L, M and Q are as defined herein. A process for the preparation of a compound of formula I is provided, characterized in that
In a fifteenth aspect of the invention, Formula 1d:

Wherein A, R ² , B, K, L, M, R ⁷ and R ⁸ are as defined herein.
An intermediate compound represented by: or a salt or derivative thereof is provided.
In the sixteenth aspect of the present invention,
a) a coupling agent in a mixture with or without a suitable solvent at a temperature of about 20 ° C. to about 170 ° C., and intermediate 1d:

Is coupled with an amine Q-NH ² to form a compound of formula I wherein A, R ² , B, R ⁷ , R ⁸ , Q, K, L, and M are as defined herein. There is provided a process for the preparation of a compound of formula I, characterized in that
In a seventeenth aspect of the present invention, the treatment of a mammalian HCV infection, comprising administering to a mammal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with another anti-HCV agent. Prophylactic methods are provided.

Definitions Unless otherwise stated, the following definitions apply.
The term “(C _1-3 ) alkyl”, “(C _1-4 ) alkyl” or “(C _1-6 ) alkyl” as used herein alone or in combination with another group is: It is intended to mean an acyclic linear or branched alkyl group containing up to 3, 4 and 6 carbon atoms, respectively. Examples of such groups include methyl, ethyl, propyl, butyl, hexyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl.
The term “(C _2-6 ) alkenyl” as used herein alone or in combination with another group means an unsaturated, acyclic linear group containing from 2 to 6 carbon atoms. Is intended to be.
The term “(C _2-6 ) alkynyl” as used herein alone or in combination with another group is an unsaturated, acyclic linear sp hybrid containing 2 to 6 carbon atoms. Is meant to mean
The term “(C _3-7 ) cycloalkyl” as used herein alone or in combination with another group means a cycloalkyl containing 3 to 7 carbon atoms, cyclopropyl, cyclobutyl , Cyclopentyl, cyclohexyl and cycloheptyl.
The term “(C _5-7 ) cycloalkenyl” as used herein alone or in combination with another group means an unsaturated cyclic group containing from 5 to 7 carbon atoms.
As used herein, the term “carboxy-protecting group” identifies a protecting group that can be used during coupling, Greene “Protecting Groups in Organic Chemistry”, John Wiley & Sons, New York (1981) and “Peptides: Analysis, Synthesis, Biology ", Volume 3, Academic Press, New York (1981), the disclosures of which are incorporated herein by reference.
The α-carboxy group of the C-terminal residue is usually protected as an ester (CPG) that can be cleaved to give the carboxylic acid. Protecting groups that may be used include 1) alkyl esters such as methyl esters, trimethylsilylethyl esters and t-butyl esters, 2) aralkyl esters such as benzyl esters and substituted benzyl esters, or 3) mild base treatment or mild. Examples include esters that can be cleaved by reducing means, such as trichloroethyl ester and phenacyl ester.

The term “aryl” or “6- or 10-membered aryl” as used herein alone or in combination with another group refers to an aromatic group containing 6 or 10 carbon atoms, such as phenyl or It means naphthyl.
As used herein, the term heteroatom means O, S or N.
The term “heterocycle” as used herein, alone or in combination with another group, is a 5-membered, 6-membered, or 7-containing 1-4 heteroatoms selected from nitrogen, oxygen and sulfur. A monovalent group derived by removal of hydrogen from a membered saturated or unsaturated (including aromatic) heterocycle. Further, as used herein, a “bicyclic heterocycle” is a heterocycle as defined above fused to one or more other rings, which may be a heterocycle or any other ring. Means. Examples of such heterocycles include pyrrolidine, tetrahydrofuran, thiazolidine, pyrrole, thiophene, coumarin, hydantoin, diazepine, 1H-imidazole, isoxazole, thiazole, tetrazole, piperidine, 1,4-dioxane, 4-morpholine, pyridine, Pyridine-N-oxide, pyrimidine, thiazolo [4,5-b] -pyridine, quinoline, or indole, or the following heterocycle:

However, it is not limited to these.
The term “9-membered or 10-membered bicyclic heterocycle” or “bicyclic heterocycle” as used herein, alone or in combination with another group, refers to one or more other rings (that is Means a heterocycle as defined above fused to a heterocycle or any other ring). Examples of such bicyclic heterocycles are thiazolo [4,5-b] -pyridine, quinoline or indole, or the following compound:

However, it is not limited to these.
As used herein, the term “Het” refers to a 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N, and S, or whenever possible O, N And a 9- or 10-membered bicyclic heterocycle having 1 to 5 heteroatoms selected from S and S.
The term “halo” as used herein means a halogen atom and includes fluorine, chlorine, bromine and iodine.
The term “haloalkyl” as used herein is intended to mean an alkyl as described above, eg, CH ₂ Br or CF ₃ , wherein each hydrogen atom may be successively substituted by a halogen atom. ing.
The term “metal halide” as used herein is intended to mean any metal bonded to a halogen atom for use in a metal catalyzed cross-coupling reaction. Examples of such metal halides include, but are not limited to, -MgCl, -CuCl, or -ZnCl.
As used herein, the term “OH” refers to a hydroxyl group. It is known to those skilled in the art that the hydroxyl group can be substituted by a functional group equivalent. Examples of such functional group equivalents contemplated by the present invention include, but are not limited to, ethers, sulfhydryls, and primary, secondary or tertiary amines.
As used herein, the term “SH” refers to a sulfhydryl group. Whenever an “SH” or “SR” group is present, it is intended within the scope of the present invention that it can be replaced by any other suitable oxidation state, eg, SOR, SO ₂ R, or SO ₃ R. Yes.
C _1-6 alkyl - aryl, or C _1-6 when applied in conjunction with groups having such one more portion of the alkyl -Het term "have been substituted" in both of such substituents It is intended to be applied to the moiety, i.e. both alkyl and aryl or Het moieties may be substituted with the specified substituents.

As used herein, the term “COOH” refers to a carboxylic acid group. It is known to those skilled in the art that carboxylic acid groups can be substituted by functional group equivalents. Examples of such functional group equivalents contemplated by the present invention include, but are not limited to, esters, amides, boronic acids or tetrazoles.
As used herein, the term “functional group equivalent” is intended to mean an element or substituted derivative thereof that can be replaced by another element having similar electrical, hybrid, or bonding properties. .
As used herein, the term “metal catalyst” is intended to mean a metal that is bound to a leaving group for use in a cross-coupling reaction, such as palladium (0) or palladium (2). Has been. Examples of such palladium catalysts include, but are not limited to, Pd (Ph ₃ ) ₄ , Pd / C, Pd (OAc) ₂ , PdCl _{2 and the} like. The cross-coupling reaction as a separate metal capable of _{catalyzing, Ni (acac) 2, Ni} (OAc) 2, or NiCl ₂ include, but are not limited to.
The term “derivative” as used herein is intended to mean “detectable label”, “affinity label” or “photoreactive group”. The term “detectable label” refers to any group capable of binding to a polymerase or a compound of the invention, so that when the compound is associated with a polymerase target, such label is a direct or indirect recognition of the compound. So that it can be detected, measured and quantified. Examples of such “labels” are intended to include, but are not limited to, fluorescent labels, chemiluminescent labels, colorimetric labels, enzyme markers, radioisotopes and affinity labels such as biotin. . Such a label is bound to the compound or polymerase by known methods. The term “affinity label” refers to a ligand (which is bound to a polymerase or a compound of the present invention) whose strong affinity for the receptor can be used to extract the entity (to which the ligand is bound) from solution. Examples of such ligands include biotin or derivatives thereof, histidine polypeptides, polyarginine, amylose sugar moieties or specific epitopes that can be recognized by specific antibodies. Such affinity labels are bound to the compound or polymerase by known methods.

The term “photoreactive group” means a group that is converted from an inert group to a reactive species, such as a free radical, after activation by light. Examples of such groups include, but are not limited to, benzophenone, azide and the like.
The term “pharmaceutically acceptable salt” as used herein includes those derived from pharmaceutically acceptable bases and is non-toxic. Examples of suitable bases include choline, ethanolamine and ethylenediamine. Na ⁺ salts, K ⁺ salts, and Ca ⁺⁺ salts are also intended to be within the scope of the present invention (and are also included herein as pharmaceutical salts, Birge, SM et al., J. Pharm Sci., (1977), 66, 1-19).
Preferred embodiment
Core:
The compounds of the present invention have the following formula (II):

(Wherein A is preferably O, S, or NR ¹ )
It is preferable to have.
A is preferably NR ¹ .
The compounds of the present invention have the following formula (III):

(In the formula, B is preferably NR ³ )
It is preferable to have.
With respect to formulas (II) and (III), M, K and L are preferably CH or N. More preferably, M, K and L are CH.
The compounds of the present invention have the following formula:

It is further preferable to have
R ¹ :
R ¹ is preferably selected from the group consisting of H or (C _1-6 ) alkyl. More preferably, R ¹ is H, CH ₃ , isopropyl, or isobutyl. More preferably, R ¹ is H or CH ₃ . Most preferably R ¹ is CH ₃ .
R ² :
Preferably, R ² is CON (R ²² ) ₂ , wherein each R ²² is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _5-7 ) Cycloalkenyl, 6-membered or 10-membered aryl or Het, or both R ²² are joined together to form a 5-, 6- or 7-membered saturated heterocycle with the nitrogen to which they are attached, or
R ² is selected from H, halogen, (C _1-6 ) alkyl, haloalkyl, (C _2-6 ) alkenyl, (C _5-7 ) cycloalkenyl, 6- or 10-membered aryl or Het, and the alkyl, haloalkyl , (C _2-6) alkenyl, (C _5-7) cycloalkenyl, the required respective aryl or Het being optionally substituted with R ^20, R ²⁰ is
1 selected from halogen, NO ₂ , cyano, azide, C (= NH) NH ₂ , C (= NH) NH (C _1-6 ) alkyl or C (= NH) NHCO (C _1-6 ) alkyl ~ 4 substituents, or
a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, (C _2-6 ) alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl (all of which may optionally be substituted with R ¹⁵⁰ ),
b) OR ^{104 wherein} R ¹⁰⁴ is H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, wherein the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is Optionally substituted with R ¹⁵⁰ ),
c) OCOR ^{105 wherein} R ¹⁰⁵ is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het, the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is optionally R ¹⁵⁰ May be substituted),
d) SR ¹⁰⁸ , SO ₂ N (R ¹⁰⁸ ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ¹⁰⁸ , wherein each R ¹⁰⁸ is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ^{108 of the above} are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6- or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het or heterocycle may be optionally substituted with R ¹⁵⁰ ),
e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ¹¹² is H, CN, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, COOR ¹¹⁵ or SO ₂ R ^{115 where} R ¹¹⁵ Is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or ( C _1-6 alkyl) Het), or both R ¹¹¹ and R ¹¹² are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-membered, 6-membered or 7-membered saturated complex. Forming a ring, said alkyl, cycloalkyl, aryl, Het, (C _1-6 Alkyl) aryl or (C _1-6 alkyl) Het, or a heterocycle optionally substituted with R ¹⁵⁰ ),

f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) Alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- ( C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹¹⁸ is covalently bound to R ¹¹⁹ and they are bound Bonded to nitrogen to form a 5-, 6-, or 7-membered saturated heterocycle, or ^R119 and ^R120 are covalently bonded together, and bonded to the nitrogen to which they are bonded, 5-membered, 6-membered Or a 7-membered saturated heterocycle, the alkyl, cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _{1- 6} alkyl) Het or heterocycle being optionally substituted with R ^0.99 if necessary),
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ and R ¹²² are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ), respectively. Cycloalkyl, 6- or 10-membered aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het is optionally substituted with R ¹⁵⁰ , or R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ , wherein R ¹²³ and each R ¹²⁴ is independently H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), or both R ¹²⁴ are covalently bonded together to form a 5-membered, 6 Forming a 7-membered or 7-membered saturated heterocyclic ring, Alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het and heterocycle optionally substituted with R ¹⁵⁰ ),
i) COR ^{127 wherein} R ¹²⁷ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het , (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is necessary ^Optionally substituted by R ¹⁵⁰ )
j) COOR ^{128 wherein} R ¹²⁸ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het , (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),

k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ¹²⁹ and R ¹³⁰ are covalently bonded together and they are bonded Combined with nitrogen to form a 5-, 6- or 7-membered saturated heterocycle, the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁵⁰ ),
l) Aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het (all of which may optionally be substituted with R ¹⁵⁰ )
R ¹⁵⁰ is preferably defined as 1 to 4 substituents selected from
1 to 3 substituents selected from halogen, NO ₂ , cyano or azide, or
a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, (C _2-6 ) alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl (all of which may optionally be substituted with R ¹⁶⁰ ),
b) OR ¹⁰⁴ (wherein R ¹⁰⁴ is H, (C _1-6 alkyl) or (C _3-7 ) cycloalkyl, and the alkyl or cycloalkyl may be optionally substituted with R ¹⁶⁰ ) ,
d) SR ¹⁰⁸ , SO ₃ H, SO ₂ N (R ¹⁰⁸ ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ¹⁰⁸ (wherein each R ¹⁰⁸ is independently H, (C _1-6 ) Alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, or both R ¹⁰⁸ are covalently bonded together and they are bonded 5- has been joined to the nitrogen which is to form a 6-membered or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, optionally substituted with R ¹⁶⁰ by Het and heterocycle necessary),

e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, or (C _3-7 ) cycloalkyl, and R ¹¹² is H, (C _1-6 ) alkyl or ( C _3-7 ) cycloalkyl, COOR ¹¹⁵ or SO ₂ R ^{115 where} R ¹¹⁵ is (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl, or R ¹¹¹ and R ¹¹² Are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6-, or 7-membered saturated heterocycle, wherein the alkyl, cycloalkyl, and heterocycle are optionally R ¹⁶⁰ May be substituted),
f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl, the (C _1-6 ) alkyl and (C _{3 -7} ) cycloalkyl may be optionally substituted with R ¹⁶⁰ ),
g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are each H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl, or R ¹¹⁸ is R ¹¹⁹ Bonded to the nitrogen to which they are bonded to form a 5-membered, 6-membered or 7-membered saturated heterocycle, or ^R119 and ^R120 are covalently bonded together and they are bonded 5- has been joined to the nitrogen which are to form a 6-membered or 7-membered saturated heterocycle, said alkyl, optionally substituted with R ¹⁶⁰ by cycloalkyl, and heterocyclic are required),
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ is H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl, and the alkyl and cycloalkyl may be optionally substituted with R ¹⁶⁰ Well, or R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ , wherein R ¹²³ and each R ¹²⁴ is independently H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl. Or both R ¹²⁴ are covalently bonded together to form a 5-, 6-, or 7-membered saturated heterocycle, wherein the alkyl, cycloalkyl, and heterocycle may be optionally substituted with R ¹⁶⁰ ) ,
i) COR ¹²⁷ (wherein R ¹²⁷ is H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl, and the alkyl and cycloalkyl may be optionally substituted with R ¹⁶⁰ ) ,
j) COOR ^{128 wherein} R ¹²⁸ is H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl, and (C _1-6 ) alkyl and (C _3-7 ) cycloalkyl are Optionally substituted with R ¹⁶⁰ ), and
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl, or both R ¹²⁹ and R ¹³⁰ together Covalently bonded to the nitrogen to which they are attached to form a 5-, 6- or 7-membered saturated heterocycle, wherein the alkyl, cycloalkyl and heterocycle may be optionally substituted with R ¹⁶⁰ Good),
1 to 3 substituents selected from

R ¹⁶⁰ is selected from halogen, CN, C _1-6 alkyl, haloalkyl, COOR ¹⁶¹ , OR ¹⁶¹ , N (R ¹⁶² ) ₂ , SO ₂ N (R ¹⁶² ) ₂ , NR ¹⁶² COR ¹⁶² or CON (R ¹⁶² ) ₂ R ¹⁶¹ and each R ¹⁶² is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _{1- 6} ) Alkyl- (C _3-7 ) cycloalkyl, or both R ¹⁶² are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6- or 7-membered saturated heterocycle Form.
More preferably, R ² is selected from aryl or Het, each optionally halogen, haloalkyl, N ₃ , or
a) (C _1-6 ) alkyl, O (C _1-6 ) alkyl or SO ₂ (C _1-6 alkyl) optionally substituted with OH if necessary,
b) (C _1-6 ) alkoxy,
e) NR ¹¹¹ R ^{112 wherein} both R ¹¹¹ and R ¹¹² are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or R ¹¹² is 6 or 10 members Aryl, Het, (C _1-6 ) alkyl-aryl or (C _1-6 ) alkyl-Het, or both R ¹¹¹ and R ¹¹² are covalently bonded together and to the nitrogen to which they are bonded. Bonded to form a nitrogen-containing heterocycle, each of said alkyl, cycloalkyl, aryl, Het, alkyl-aryl or alkyl-Het is optionally halogen or —OR ^2h or N (R ^2h ) ₂ (wherein each R ^2h is independently H, (C _1-6 ) alkyl, or both R ^2h are covalently bonded together and bound to the nitrogen to which they are attached to form a nitrogen-containing heterocycle) May be substituted)
f) NHCOR ^{117 wherein} R ¹¹⁷ is (C _1-6 ) alkyl, O (C _1-6 ) alkyl or O (C _3-7 ) cycloalkyl,
i) CO-aryl, and
k) Mono- or di-substituted with a substituent selected from the group consisting of CONH ₂ , CONH (C _1-6 alkyl), CON (C _1-6 alkyl) ₂ , CONH-aryl, or CONHC _1-6 alkylaryl May be.

More preferably, R ² is aryl or Het, each optionally halogen, haloalkyl, or
a) (C _1-6 ) alkyl, O (C _1-6 ) alkyl or SO ₂ (C _1-6 alkyl) optionally substituted with OH if necessary,
b) (C _1-6 ) alkoxy, and
e) NR ¹¹¹ R ^{112 wherein} both R ¹¹¹ and R ¹¹² are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or R ¹¹² is 6 or 10 members Aryl, Het, (C _1-6 ) alkyl-aryl or (C _1-6 ) alkyl-Het, or both R ¹¹¹ and R ¹¹² are covalently bonded together and to the nitrogen to which they are bonded. Bonded to form a nitrogen-containing heterocycle, each of said alkyl, cycloalkyl, aryl, Het, alkyl-aryl or alkyl-Het is optionally halogen or —OR ^2h or N (R ^2h ) ₂ (wherein each R ^2h is independently H, (C _1-6 ) alkyl, or both R ^2h are covalently bonded together and bound to the nitrogen to which they are attached to form a nitrogen-containing heterocycle) May be substituted)
It may be mono- or di-substituted with a substituent selected from the group consisting of
R ² is phenyl or

More preferred is a heterocycle selected from: all of which may be optionally substituted as defined above.
R ² is H, Br, CONHCH ₃ , CON (CH ₃ ) ₂ , CONH ₂ , CH = CH ₂ ,

More preferably, it is selected from the group consisting of
R ² is

More preferably, it is chosen from.
R ² is

Most preferably, it is selected from
R ³ :
R ³ is selected from (C _3-7 ) cycloalkyl, (C _3-7 ) cycloalkenyl, (C _6-10 ) bicycloalkyl, (C _6-10 ) bicycloalkenyl, 6- or 10-membered aryl, or Het It is preferable that More preferably, R ³ is (C _3-7 ) cycloalkyl. Most preferably R ³ is cyclopentyl or cyclohexyl.
Y:
Y ¹ is preferably O.
Z:
Preferably, Z is OR ⁶ where R ⁶ is
a) (C _1-6 ) alkyl, haloalkyl, (C _3-7 ) cycloalkyl substituted with R ^150a , C _3-7 spirocycloalkyl optionally containing 1 or 2 heteroatoms , (C _2-6 ) alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl (said haloalkyl, cycloalkyl, spirocycloalkyl, alkenyl, alkynyl and alkyl- Cycloalkyl may be optionally substituted with R ¹⁵⁰ , and R ^150a is COOR ^150b , N (R ^150b ) ₂ , NR ^150b C (O) R ^150b , OR ^150b , SR ^150b , SO ₂ R ^150b , SO ₂ N (R ^150b ) is the same as R ¹⁵⁰ except that it is not ₂ , and R ^150b is H or unsubstituted C _1-6 alkyl)
b) OR ¹⁰⁴ (where R ¹⁰⁴ is (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cyclo) substituted with R ¹⁵⁰ Alkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, said cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
d) SR ^108a , SO ₂ N (R ^108a ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ¹⁰⁸ , wherein each R ¹⁰⁸ is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ^{108 of the above} are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6- or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het or heterocycle may be optionally substituted with R ¹⁵⁰ and R ^108a is the same as R ¹⁰⁸ except that it is not H or unsubstituted C _1-6 alkyl ),

e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ¹¹² is H, CN, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, provided that R ¹¹¹ is H or unsubstituted alkyl In some cases, provided that R ¹¹² is not H or unsubstituted alkyl, or R ¹¹² is also COOR ¹¹⁵ or SO ₂ R ^{115a where} R ¹¹⁵ is H, (C _1-6 ) alkyl, ( C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ^115a, except not H or unsubstituted alkyl is the same as R ¹¹⁵ , And the or both by R ¹¹¹ and R ¹¹² are covalently bonded together, and 5-membered has been joined to the nitrogen to which they are attached form a 6-membered or 7-membered saturated heterocycle, said alkyl, cycloalkyl , Aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or a heterocycle may be optionally substituted with R ¹⁵⁰ ),
f) NR ¹¹⁶ COR ¹¹⁷ (wherein, R ¹¹⁶ and R ¹¹⁷ is substituted with each R ¹⁵⁰ (C _1-6) alkyl, (C _3-7) cycloalkyl, (C _1-6) alkyl - (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- ( C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),

g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- ( C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹¹⁸ is covalently bound to R ¹¹⁹ and they are bound Bonded to nitrogen to form a 5-, 6-, or 7-membered saturated heterocycle, or ^R119 and ^R120 are covalently bonded together, and bonded to the nitrogen to which they are bonded, 5-membered, 6-membered Or a 7-membered saturated heterocycle, the alkyl, cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _{1- 6} alkyl) Het or heterocycle being optionally substituted with R ^0.99 if necessary),
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ is H or (C _1-6 ) alkyl and R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ , wherein R ¹²³ and the respective R ¹²⁴ is independently H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 Alkyl) aryl or (C _1-6 alkyl) Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), or both R ¹²⁴ are covalently bonded together to form 5-membered, 6-membered or Forming a 7-membered saturated heterocycle, wherein the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het and heterocycle are optionally R ¹⁵⁰ May be substituted),
j) COOR ^{128 wherein} R ¹²⁸ is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl substituted with R ¹⁵⁰ , Aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, provided that when R ¹²⁹ is H or unsubstituted alkyl, R ¹³⁰ is H or Provided that it is not a substituted alkyl, or both R ¹²⁹ and R ¹³⁰ are covalently bonded together and bonded to the nitrogen to which they are attached to form a 5-, 6- or 7-membered saturated heterocycle. , The alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het and heterocycle may be optionally substituted with R ¹⁵⁰ ),

l) Aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het (all of which may optionally be substituted with R ¹⁵⁰ )
R ¹⁵⁰ is (C _1-6 alkyl) aryl substituted with 1 to 4 substituents selected from
1 to 3 substituents selected from halogen or azide, or
a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, C _3-7 spirocycloalkyl optionally containing 1 or 2 heteroatoms, (C _2-6 ) Alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl (all of which may optionally be substituted with R ¹⁶⁰ ),
b) OR ^{104 wherein} R ¹⁰⁴ is H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, wherein the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is Optionally substituted with R ¹⁶⁰ ),
d) SR ¹⁰⁸ , SO ₂ N (R ¹⁰⁸ ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ¹⁰⁸ , wherein each R ¹⁰⁸ is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ^{108 of the above} are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6- or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het or heterocycle being optionally substituted with R ¹⁶⁰ as required),
e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ¹¹² is H, CN, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, COOR ¹¹⁵ or SO ₂ R ^{115 where} R ¹¹⁵ Is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or ( C _1-6 alkyl) Het), or both R ¹¹¹ and R ¹¹² are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-membered, 6-membered or 7-membered saturated complex. Forming a ring, said alkyl, cycloalkyl, aryl, Het, (C _1-6 Alkyl) aryl or (C _1-6 alkyl) Het, or a heterocycle optionally substituted with R ¹⁶⁰ ),

f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) Alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁶⁰ ),
g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- ( C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹¹⁹ and R ¹²⁰ are covalently bonded together and they are bonded To form a 5-membered, 6-membered or 7-membered saturated heterocyclic ring, and the alkyl, cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, ( C _1-6 alkyl) aryl or (C _1-6 alkyl) Het or heterocycle may be optionally substituted with R ¹⁶⁰ ),
h) NR ¹²¹ COCOR ^{122 where} R ¹²¹ is H, (C _1-6 ) alkyl, and R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ , wherein R ¹²³ and the respective R ¹²⁴ is independently H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 Alkyl) aryl or (C _1-6 alkyl) Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), or both R ¹²⁴ are covalently bonded together to form 5-membered, 6-membered or Forming a 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het and heterocycle optionally in R ¹⁶⁰ May be substituted),
j) Tetrazole, COOR ¹²⁸ (wherein R ¹²⁸ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl) , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁶⁰ ), and

k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ¹²⁹ and R ¹³⁰ are covalently bonded together and they are bonded Combined with nitrogen to form a 5-, 6- or 7-membered saturated heterocycle, the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁶⁰ ),
1 to 3 substituents selected from
R ¹⁶⁰ is tetrazole, halogen, CN, C _1-6 alkyl, haloalkyl, COOR ¹⁶¹ , SO ₃ H, SO ₂ R ¹⁶¹ , OR ¹⁶¹ , N (R ¹⁶² ) ₂ , SO ₂ N (R ¹⁶² ) ₂ , NR ¹⁶² It is defined as one or two substituents selected from COR ¹⁶² or CON (R ¹⁶² ) ₂ , wherein R ¹⁶¹ and R ¹⁶² are as defined above.
More preferably, Z is OR ⁶ where R ⁶ is
a) (C _1-6 ) alkyl, haloalkyl, (C _3-7 ) cycloalkyl substituted with R ^150a , C _3-7 spirocycloalkyl optionally containing 1 or 2 heteroatoms , (C _2-6 ) alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl (said haloalkyl, cycloalkyl, spirocycloalkyl, alkenyl, alkynyl and alkyl- Cycloalkyl may be optionally substituted with R ¹⁵⁰ , and R ^150a is COOR ^150b , N (R ^150b ) ₂ , NR ^150b C (O) R ^150b , OR ^150b , SR ^150b , SO ₂ R ^150b , SO ₂ N (R ^150b ) is the same as R ¹⁵⁰ except that it is not ₂ , and R ^150b is H or unsubstituted C _1-6 alkyl)
b) OR ¹⁰⁴ (where R ¹⁰⁴ is (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cyclo) substituted with R ¹⁵⁰ Alkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, said cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),

d) SO ₃ H, SO ₂ N (R ^108a ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ^{108 where} each R ¹⁰⁸ is independently H, (C _1-6 ) alkyl and aryl The alkyl and aryl may be optionally substituted with R ¹⁵⁰ , and R ^108a is the same as R ¹⁰⁸ except that it is not H or unsubstituted C _1-6 alkyl)
e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ¹¹² is H, (C _1-6 ) alkyl, provided that R ¹¹¹ is H or unsubstituted alkyl. In some instances, R ¹¹² is not H or unsubstituted alkyl, or R ¹¹² is also COOR ¹¹⁵ or SO ₂ R ^{115a where} R ¹¹⁵ is H, (C _1-6 ) alkyl or ( C _1-6 alkyl) aryl and R ^115a is C _1-6 alkyl or (C _1-6 alkyl) aryl substituted with R ¹⁵⁰ ), or both R ¹¹¹ and R ¹¹² are together To the nitrogen to which they are attached to form a 5-membered, 6-membered or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _{1 -6A} Alkyl) aryl or (C _1-6 alkyl) Het, or a heterocycle optionally substituted with R ¹⁵⁰ ),
f) NR ¹¹⁶ COR ¹¹⁷ (wherein, R ¹¹⁶ and R ¹¹⁷ is substituted with each R ¹⁵⁰ (C _1-6) alkyl, (C _3-7) cycloalkyl, aryl, Het, said (C _{3 -7} ) cycloalkyl, aryl, Het may be optionally substituted with R ¹⁵⁰ ),
g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are H, (C _1-6 ) alkyl, aryl and Het, said alkyl, aryl and Het are optionally R ¹⁵⁰ May be substituted),
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ is H or (C _1-6 ) alkyl and R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ , wherein R ¹²³ and the respective R ¹²⁴ is independently H, (C _1-6 alkyl), aryl or Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), wherein the alkyl, aryl and Het are optionally substituted with R ¹⁵⁰ May be)
j) COOR ¹²⁸ (wherein R ¹²⁸ is (C _1-6 ) alkyl substituted with R ¹⁵⁰ ),
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, aryl or Het, provided that when R ¹²⁹ is H or unsubstituted alkyl, R ¹³⁰ is not H or unsubstituted alkyl, and the alkyl, aryl and Het may be optionally substituted with R ¹⁵⁰ ),

l) Aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het (all of which may optionally be substituted with R ¹⁵⁰ )
R ¹⁵⁰ is (C _1-6 alkyl) aryl substituted with 1 to 4 substituents selected from
1 to 3 substituents selected from halogen or azide, or
a) (C _1-6 ) alkyl or haloalkyl, (C _2-6 ) alkenyl (all of which may optionally be substituted with R ¹⁶⁰ ),
b) OR ¹⁰⁴ (wherein R ¹⁰⁴ is H, (C _1-6 alkyl), aryl or Het, and the alkyl, aryl and Het may be optionally substituted with R ¹⁶⁰ ),
d) SR ¹⁰⁸ , SO ₂ N (R ¹⁰⁸ ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ^{108 where} each R ¹⁰⁸ is independently H, (C _1-6 ) alkyl, aryl or Het, wherein the alkyl, aryl and Het may be optionally substituted with R ¹⁶⁰ ),
e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, aryl or Het and R ¹¹² is H, (C _1-6 ) alkyl, COOR ¹¹⁵ or SO ₂ R ¹¹⁵ Wherein R ¹¹⁵ is (C _1-6 ) alkyl, and the alkyl, aryl or Het may be optionally substituted with R ¹⁶⁰ ),
f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each H, (C _1-6 ) alkyl, aryl or Het, and said alkyl, aryl and Het may be optionally substituted with R ¹⁶⁰ Good),
g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are each H, (C _1-6 ) alkyl, aryl or Het, wherein said alkyl, aryl and Het are optionally R ¹⁶⁰ May be substituted),

h) NR ¹²¹ COCOR ^{122 where} R ¹²¹ is H, (C _1-6 ) alkyl, and R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ , wherein R ¹²³ and the respective R ¹²⁴ is independently H, (C _1-6 alkyl), aryl or Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), wherein the alkyl, aryl and Het are optionally substituted with R ¹⁶⁰ May be)
j) tetrazole, COOR ^{128 where} R ¹²⁸ is H, optionally substituted with R ¹⁶⁰ ((C _1-6 ) alkyl), and
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, aryl or Het, wherein said alkyl, aryl and Het are optionally substituted with R ¹⁶⁰ May be)
1 to 3 substituents selected from
R ¹⁶⁰ is tetrazole, halogen, CN, C _1-6 alkyl, haloalkyl, COOR ¹⁶¹ , SO ₃ H, SO ₂ R ¹⁶¹ , OR ¹⁶¹ , N (R ¹⁶² ) ₂ , SO ₂ N (R ¹⁶² ) ₂ , NR ¹⁶² It is defined as one or two substituents selected from COR ¹⁶² or CON (R ¹⁶² ) ₂ , wherein R ¹⁶¹ and R ¹⁶² are as defined above.
More preferably, Z is OR ⁶ , wherein R ⁶ is (C _2-6 ) alkenyl, (C _1-6 ) alkyl-Het, said alkenyl or alkyl-Het optionally substituted with R ⁶⁰ R ⁶⁰ may be
1 to 4 substituents selected from -halogen, or
a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, C _3-7 spirocycloalkyl optionally containing 1 or 2 heteroatoms, (C _2-6 ) alkenyl , (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl (all of which may optionally be substituted with R ¹⁵⁰ ),
b) OR ^{104 wherein} R ¹⁰⁴ is H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, wherein the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is Optionally substituted with R ¹⁵⁰ ),

d) SR ¹⁰⁸ , SO ₂ N (R ¹⁰⁸ ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ¹⁰⁸ , wherein each R ¹⁰⁸ is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ^{108 of the above} are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6- or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het or heterocycle may be optionally substituted with R ¹⁵⁰ ),
e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ¹¹² is H, CN, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, COOR ¹¹⁵ or SO ₂ R ^{115 where} R ¹¹⁵ Is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or ( C _1-6 alkyl) Het), or both R ¹¹¹ and R ¹¹² are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-membered, 6-membered or 7-membered saturated complex. Forming a ring, said alkyl, cycloalkyl, aryl, Het, (C _1-6 Alkyl) aryl or (C _1-6 alkyl) Het, or a heterocycle optionally substituted with R ¹⁵⁰ ),
f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, respectively. , Aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl -(C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is optionally substituted with R ¹⁵⁰ ),

g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- ( C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹¹⁸ is covalently bound to R ¹¹⁹ and they are bound Bonded to nitrogen to form a 5-, 6-, or 7-membered saturated heterocycle, or ^R119 and ^R120 are covalently bonded together, and bonded to the nitrogen to which they are bonded, 5-membered, 6-membered Or a 7-membered saturated heterocycle, the alkyl, cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _{1- 6} alkyl) Het or heterocycle being optionally substituted with R ^0.99 if necessary),
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ is H, (C _1-6 ) alkyl optionally substituted with R ¹⁵⁰ and R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ Wherein R ¹²³ and each R ¹²⁴ are independently H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cyclo Alkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), or both R ¹²⁴ are together To form a 5-membered, 6-membered or 7-membered saturated heterocyclic ring, and the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁵⁰ ),
i) COR ^{127 wherein} R ¹²⁷ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het , (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is necessary ^Optionally substituted by R ¹⁵⁰ )
j) COOR ^{128 wherein} R ¹²⁸ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het , (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),

k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ¹²⁹ and R ¹³⁰ are covalently bonded together and they are bonded Combined with nitrogen to form a 5-, 6- or 7-membered saturated heterocycle, the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁵⁰ ),
l) Aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het (all of which may optionally be substituted with R ¹⁵⁰ )
1 to 4 substituents selected from: R ¹⁵⁰ is
1 to 3 substituents selected from halogen or azide, or
a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, C _3-7 spirocycloalkyl optionally containing 1 or 2 heteroatoms, (C _2-6 ) alkenyl , (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl (all of which may optionally be substituted with R ¹⁶⁰ ),
b) OR ^{104 wherein} R ¹⁰⁴ is H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, said alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) -Het ^{May be} optionally substituted with R ¹⁶⁰ ),
d) SR ¹⁰⁸ , SO ₂ N (R ¹⁰⁸ ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ¹⁰⁸ , wherein each R ¹⁰⁸ is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ^{108 of the above} are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6- or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het or heterocycle being optionally substituted with R ¹⁶⁰ as required),

e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ¹¹² is H, CN, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, COOR ¹¹⁵ or SO ₂ R ^{115 where} R ¹¹⁵ Is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or ( C _1-6 alkyl) Het), or both R ¹¹¹ and R ¹¹² are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-membered, 6-membered or 7-membered saturated complex. Forming a ring, said alkyl, cycloalkyl, aryl, Het, (C _1-6 Alkyl) aryl or (C _1-6 alkyl) Het, or a heterocycle optionally substituted with R ¹⁶⁰ ),
f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) Alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁶⁰ ),
g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- ( C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹¹⁸ is covalently bound to R ¹¹⁹ and they are bound Bonded to nitrogen to form a 5-, 6-, or 7-membered saturated heterocycle, or ^R119 and ^R120 are covalently bonded together and bonded to the nitrogen to which they are bonded, 5-membered, 6-membered Or a 7-membered saturated heterocyclic ring, and the alkyl, cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _{1- 6} alkyl) Het or heterocycle being optionally substituted with R ¹⁶⁰ as required),

h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ is H or (C _1-6 ) alkyl optionally substituted with R ¹⁶⁰ and R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ Wherein R ¹²³ and each R ¹²⁴ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cyclo Alkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), or both R ¹²⁴ are together To form a 5-membered, 6-membered or 7-membered saturated heterocyclic ring, and the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁶⁰ ),
j) Tetrazole, COOR ¹²⁸ (wherein R ¹²⁸ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, Aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl -(C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁶⁰ ), and
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) -Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ¹²⁹ and R ¹³⁰ are covalently bonded together and they are bonded To form a 5-membered, 6-membered or 7-membered saturated heterocyclic ring, and the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 Alkyl) Het and heterocycle may be optionally substituted with R ¹⁶⁰ ),
Defined as 1 to 3 substituents selected from
R ¹⁶⁰ is tetrazole, halogen, CN, C _1-6 alkyl, haloalkyl, COOR ¹⁶¹ , SO ₃ H, SR ¹⁶¹ , SO ₂ R ¹⁶¹ , OR ¹⁶¹ , N (R ¹⁶² ) ₂ , SO ₂ N (R ¹⁶² ) ₂ , NR ¹⁶² COR ¹⁶² or CON (R ¹⁶² ) ₂ defined as one or two substituents, wherein R ¹⁶¹ and each R ¹⁶² are independently H, (C _1-6 ) alkyl , (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, or both R ¹⁶² are covalently bonded together and to the nitrogen to which they are bonded. Combined to form a 5-, 6- or 7-membered saturated heterocycle.

More preferably, R ⁶⁰ is
1 to 4 substituents selected from -halogen, or
a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, C _3-7 spirocycloalkyl optionally containing 1 or 2 heteroatoms, (C _2-6 ) alkenyl , (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl (all of which may optionally be substituted with R ¹⁵⁰ ),
b) OR ^{104 wherein} R ¹⁰⁴ is H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, wherein the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is Optionally substituted with R ¹⁵⁰ ),
d) SO ₃ H, SO ₂ N (R ¹⁰⁸ ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ¹⁰⁸ , wherein each R ¹⁰⁸ is independently H, (C _1-6 ) alkyl or aryl The alkyl and aryl may be optionally substituted with R ¹⁵⁰ ),
e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ¹¹² is H, (C _1-6 ) alkyl, COOR ¹¹⁵ or SO ₂ R ¹¹⁵ (wherein R ¹¹⁵ Is (C _1-6 ) alkyl or (C _1-6 alkyl) aryl), or both R ¹¹¹ and R ¹¹² are covalently bonded together and bonded to the nitrogen to which they are bonded. Forms a 5-membered, 6-membered or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or a heterocycle optionally R ¹⁵⁰ may be substituted)
f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, aryl or Het, and the (C _1-6 ) alkyl, ( C _3-7 ) cycloalkyl, aryl or Het is optionally substituted with R ¹⁵⁰ ),

g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are each H, (C _1-6 ) alkyl, aryl or Het, wherein said alkyl, aryl and Het are optionally R ¹⁵⁰ May be substituted),
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ is H or (C _1-6 ) alkyl and R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ , wherein R ¹²³ and the respective R ¹²⁴ is independently H, (C _1-6 alkyl), aryl or Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), wherein the alkyl, aryl and Het are optionally substituted with R ¹⁵⁰ May be)
j) COOR ¹²⁸ (wherein R ¹²⁸ is H or (C _1-6 ) alkyl optionally substituted with R ¹⁵⁰ ),
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, aryl or Het, wherein said alkyl, aryl and Het are optionally substituted with R ¹⁵⁰ May be)
l) Aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het (all of which may optionally be substituted with R ¹⁵⁰ )
1 to 4 substituents selected from: R ¹⁵⁰ is
1 to 3 substituents selected from -halogen, or

a) (C _1-6 ) alkyl or haloalkyl, (C _2-6 ) alkenyl (all of which may optionally be substituted with R ¹⁶⁰ ),
b) OR ¹⁰⁴ (wherein R ¹⁰⁴ is H, (C _1-6 alkyl), aryl or Het, and the alkyl, aryl and Het may be optionally substituted with R ¹⁶⁰ ),
d) SR ¹⁰⁸ , SO ₂ N (R ¹⁰⁸ ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ^{108 where} each R ¹⁰⁸ is independently H, (C _1-6 ) alkyl, aryl or Het, wherein the alkyl, aryl and Het may be optionally substituted with R ¹⁶⁰ ),
e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, aryl or Het and R ¹¹² is H, (C _1-6 ) alkyl, COOR ¹¹⁵ or SO ₂ R ¹¹⁵ Wherein R ¹¹⁵ is (C _1-6 ) alkyl or aryl, and the alkyl, aryl and Het may be optionally substituted with R ¹⁶⁰ ),
f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each H, (C _1-6 ) alkyl, aryl or Het, and said alkyl, aryl and Het may be optionally substituted with R ¹⁶⁰ Good),
g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are each H, (C _1-6 ) alkyl, aryl or Het, wherein said alkyl, aryl and Het are optionally R ¹⁶⁰ May be substituted),
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ is H or (C _1-6 ) alkyl optionally substituted with R ¹⁶⁰ and R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ Wherein R ¹²³ and each R ¹²⁴ is independently H, (C _1-6 ) alkyl, aryl or Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), , Aryl and Het may be optionally substituted with R ¹⁶⁰ ),
j) tetrazole, COOR ^{128 where} R ¹²⁸ is H or (C _1-6 ) alkyl optionally substituted with R ¹⁶⁰ , and
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, aryl or Het, wherein said alkyl, aryl and Het are optionally substituted with R ¹⁶⁰ May be)
Defined as 1 to 3 substituents selected from
R ¹⁶⁰ is tetrazole, halogen, CN, C _1-6 alkyl, haloalkyl, COOR ¹⁶¹ , SO ₃ H, SR ¹⁶¹ , SO ₂ R ¹⁶¹ , OR ¹⁶¹ , N (R ¹⁶² ) ₂ , SO ₂ N (R ¹⁶² ) ₂ , NR ¹⁶² COR ¹⁶² or CON (R ¹⁶² ) ₂ defined as one or two substituents, wherein R ¹⁶¹ and each R ¹⁶² are independently H, (C _1-6 ) alkyl , (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, or both R ¹⁶² are covalently bonded together and to the nitrogen to which they are bonded. Combined to form a 5-, 6- or 7-membered saturated heterocycle.

Most preferably, Z is N (R ^6a ) R ⁶ where R ^6a is H or C _1-6 alkyl. More preferably, R ^6a is H.
Preferably, R ⁶ is (C _2-6 ) alkenyl, aryl, Het, (C _1-6 ) alkyl-aryl, (C _1-6 ) alkyl-Het, said alkenyl, aryl, Het, alkyl-aryl Or all alkyl-Het as needed
-From halogen, OPO ₃ H, NO ₂ , cyano, azide, C (= NH) NH ₂ , C (= NH) NH (C _1-6 ) alkyl or C (= NH) NHCO (C _1-6 ) alkyl 1 to 4 selected substituents, or
a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, C _3-7 spirocycloalkyl optionally containing 1 or 2 heteroatoms, (C _2-6 ) Alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl (all of which may optionally be substituted with R ¹⁵⁰ ),
b) OR ^{104 wherein} R ¹⁰⁴ is H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, wherein the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is Optionally substituted with R ¹⁵⁰ ),
d) SR ¹⁰⁸ , SO ₂ NH (C _1-6 alkyl) or SO ₂ NHC (O) C _1-6 alkyl,

e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ¹¹² is H, CN, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, COOR ¹¹⁵ or SO ₂ R ^{115 where} R ¹¹⁵ Is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or ( C _1-6 alkyl) Het), or both R ¹¹¹ and R ¹¹² are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-membered, 6-membered or 7-membered saturated complex. Forming a ring, said alkyl, cycloalkyl, aryl, Het, (C _1-6 Alkyl) aryl or (C _1-6 alkyl) Het, or a heterocycle optionally substituted with R ¹⁵⁰ ),
f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) Alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- ( C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹¹⁸ is covalently bound to R ¹¹⁹ and they are bound Bonded to nitrogen to form a 5-, 6-, or 7-membered saturated heterocycle, or ^R119 and ^R120 are covalently bonded together, and bonded to the nitrogen to which they are bonded, 5-membered, 6-membered Or a 7-membered saturated heterocycle, the alkyl, cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _{1- 6} alkyl) Het or heterocycle being optionally substituted with R ^0.99 if necessary),
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ and R ¹²² are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ), respectively. Cycloalkyl, 6- or 10-membered aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het is optionally substituted with R ¹⁵⁰ , or R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ , wherein R ¹²³ and each R ¹²⁴ is independently H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), or both R ¹²⁴ are covalently bonded together to form a 5-membered, 6 Forming a 7-membered or 7-membered saturated heterocyclic ring, Alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het and heterocycle optionally substituted with R ¹⁵⁰ ),

i) COR ^{127 wherein} R ¹²⁷ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het , (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is necessary ^Optionally substituted by R ¹⁵⁰ )
j) COOR ^{128 wherein} R ¹²⁸ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het , (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ¹²⁹ and R ¹³⁰ are covalently bonded together and they are bonded Combined with nitrogen to form a 5-, 6- or 7-membered saturated heterocycle, the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁵⁰ ),
l) Aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het (all of which may optionally be substituted with R ¹⁵⁰ )
It may be substituted by 1-4 substituents selected from, preferably, R ^0.99 is
1 to 3 substituents selected from halogen, NO ₂ , cyano or azide, or

a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, C _3-7 spirocycloalkyl optionally containing 1 or 2 heteroatoms, (C _2-6 ) Alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl (all of which may optionally be substituted with R ¹⁶⁰ ),
b) OR ^{104 wherein} R ¹⁰⁴ is H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, wherein the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is Optionally substituted with R ¹⁶⁰ ),
d) SR ¹⁰⁸ , SO ₂ N (R ¹⁰⁸ ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ¹⁰⁸ , wherein each R ¹⁰⁸ is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ^{108 of the above} are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6- or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het or heterocycle being optionally substituted with R ¹⁶⁰ as required),
e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ¹¹² is H, CN, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, COOR ¹¹⁵ or SO ₂ R ^{115 where} R ¹¹⁵ Is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or ( C _1-6 alkyl) Het), or both R ¹¹¹ and R ¹¹² are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-membered, 6-membered or 7-membered saturated complex. Forming a ring, said alkyl, cycloalkyl, aryl, Het, (C _1-6 Alkyl) aryl or (C _1-6 alkyl) Het, or a heterocycle optionally substituted with R ¹⁶⁰ ),

f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) Alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁶⁰ ),
g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- ( C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹¹⁸ and R ¹¹⁹ are covalently bonded together and they are bonded To form a 5-membered, 6-membered or 7-membered saturated heterocyclic ring, and the alkyl, cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, ( C _1-6 alkyl) aryl or (C _1-6 alkyl) Het or heterocycle may be optionally substituted with R ¹⁶⁰ ),
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ is H or (C _1-6 ) alkyl optionally substituted with R ¹⁶⁰ and R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ Wherein R ¹²³ and each R ¹²⁴ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cyclo Alkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), or both R ¹²⁴ are together To form a 5-membered, 6-membered or 7-membered saturated heterocyclic ring, and the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁶⁰ ),

j) Tetrazole, COOR ¹²⁸ (wherein R ¹²⁸ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl) , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁶⁰ ), and
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ¹²⁹ and R ¹³⁰ are covalently bonded together and they are bonded Combined with nitrogen to form a 5-, 6- or 7-membered saturated heterocycle, the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁶⁰ ),
Selected from 1 to 3 substituents selected from
R ¹⁶⁰ is tetrazole, halogen, CN, C _1-6 alkyl, haloalkyl, COOR ¹⁶¹ , SO ₃ H, SO ₂ R ¹⁶¹ , OR ¹⁶¹ , N (R ¹⁶² ) ₂ , SO ₂ N (R ¹⁶² ) ₂ , NR ¹⁶² Defined as one or two substituents selected from COR ¹⁶² or CON (R ¹⁶² ) ₂ , wherein R ¹⁶¹ and each R ¹⁶² are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, or both R ¹⁶² are covalently bonded together and bound to the nitrogen to which they are bound. Form a 5-, 6- or 7-membered saturated heterocycle.

More preferably, R ⁶ is (C _2-6 ) alkenyl, aryl, Het, (C _1-6 ) alkyl-aryl, (C _1-6 ) alkyl-Het, said alkenyl, aryl, Het, alkyl- Aryl or alkyl-Het is all necessary
1 to 4 substituents selected from halogen, NO ₂ , cyano, azide, or
a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, C _3-7 spirocycloalkyl optionally containing 1 or 2 heteroatoms, (C _2-6 ) Alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl (all of which may optionally be substituted with R ¹⁵⁰ ),
b) OR ^{104 wherein} R ¹⁰⁴ is H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, wherein the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is Optionally substituted with R ¹⁵⁰ ),
d) SH, S (C _1-6 alkyl), SO ₃ H, SO ₂ NH (C _1-6 alkyl) or SO ₂ NHC (O) C _1-6 alkyl,
e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ¹¹² is H, CN, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, COOR ¹¹⁵ or SO ₂ R ^{115 where} R ¹¹⁵ Is (C _1-6 ) alkyl), or both R ¹¹¹ and R ¹¹² are covalently bonded together and bonded to the nitrogen to which they are bonded to be 5-membered, 6-membered or 7-membered saturated A heterocyclic ring is formed, and the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or the heterocyclic ring may be optionally substituted with R ¹⁵⁰ ) ,
f) NR ¹¹⁶ COR ¹¹⁷ (wherein R ¹¹⁶ and R ¹¹⁷ are each H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, the (C _1-6 ) alkyl, (C _{3 -7} ) cycloalkyl may be optionally substituted with R ¹⁵⁰ ),

g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are each H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or R ¹¹⁹ and R ¹²⁰ are Covalently bonded together and bonded to the nitrogen to which they are attached to form a 5-, 6-, or 7-membered saturated heterocycle, wherein said alkyl, cycloalkyl, or heterocycle is optionally substituted with R ¹⁵⁰ You may)
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, and the alkyl and cycloalkyl may be optionally substituted with R ¹⁵⁰ Well, or R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ , wherein R ¹²³ and each R ¹²⁴ is independently H, (C _1-6 alkyl) or (C _3-7 ) cycloalkyl. Or R ¹²⁴ is OH or O (C _1-6 alkyl), or both R ¹²⁴ are covalently bonded together to form a 5-, 6- or 7-membered saturated heterocycle, said alkyl, cyclo Alkyl and heterocycle may be optionally substituted with R ¹⁵⁰ ),
j) COOR ^{128 wherein} R ¹²⁸ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het , (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) Aryl and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
l) Aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het (all of which may optionally be substituted with R ¹⁵⁰ )
It may be substituted by 1-4 substituents selected from, preferably, R ^0.99 is
1 to 3 substituents selected from halogen, NO ₂ , cyano or azide, or

a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, C _3-7 spirocycloalkyl optionally containing 1 or 2 heteroatoms, (C _2-6 ) Alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl (all of which may optionally be substituted with R ¹⁶⁰ ),
b) OR ^{104 wherein} R ¹⁰⁴ is H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, wherein the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is Optionally substituted with R ¹⁶⁰ ),
d) SH, S (C _1-6 alkyl), SO ₃ H, SO ₂ N (R ¹⁰⁸ ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ¹⁰⁸ (where each R ¹⁰⁸ is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or ( C _1-6 alkyl) Het, or both R ¹⁰⁸ are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6-, or 7-membered saturated heterocycle, Alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het or a heterocycle optionally substituted with R ¹⁶⁰ ),
e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ¹¹² is H, CN, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, COOR ¹¹⁵ or SO ₂ R ^{115 where} R ¹¹⁵ Is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or ( C _1-6 alkyl) Het), or both R ¹¹¹ and R ¹¹² are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-membered, 6-membered or 7-membered saturated complex. Forming a ring, said alkyl, cycloalkyl, aryl, Het, (C _1-6 Alkyl) aryl or (C _1-6 alkyl) Het, or a heterocycle optionally substituted with R ¹⁶⁰ ),

f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) Alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁶⁰ ),
g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- ( C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹¹⁹ and R ¹²⁰ are covalently bonded together and they are bonded To form a 5-membered, 6-membered or 7-membered saturated heterocyclic ring, and the alkyl, cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, ( C _1-6 alkyl) aryl or (C _1-6 alkyl) Het or heterocycle may be optionally substituted with R ¹⁶⁰ ),
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ is H, (C _1-6 ) alkyl optionally substituted with R ¹⁶⁰ , and R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ Wherein R ¹²³ and each R ¹²⁴ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cyclo Alkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), or both R ¹²⁴ are together To form a 5-membered, 6-membered or 7-membered saturated heterocyclic ring, and the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁶⁰ ),
j) Tetrazole, COOR ¹²⁸ (wherein R ¹²⁸ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl) , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁶⁰ ), and
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ¹²⁹ and R ¹³⁰ are covalently bonded together and they are bonded Combined with nitrogen to form a 5-, 6- or 7-membered saturated heterocycle, the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) ) Het and heterocycle may be substituted by R ¹⁶⁰ necessary)
Selected from 1 to 3 substituents selected from
Preferably, R ¹⁶⁰ is tetrazole, halogen, CN, C _1-6 alkyl, haloalkyl, COOR ¹⁶¹ , SO ₃ H, SO ₂ R ¹⁶¹ , OR ¹⁶¹ , N (R ¹⁶² ) ₂ , SO ₂ N (R ¹⁶² ) ₂ , NR ¹⁶² COR ¹⁶² or CON (R ¹⁶² ) ₂ defined as one or two substituents, wherein R ¹⁶¹ and each R ¹⁶² are independently H or (C _1-6 ) alkyl. It is.

Most preferably, R ⁶ is C _2-6 alkenyl, phenyl, (C _1-6 ) alkyl-aryl, (C _1-6 ) alkyl-Het, wherein said alkenyl, phenyl and said alkyl-aryl or alkyl-Het The alkyl part of
a) (C _1-6 ) alkyl, C _3-7 spirocycloalkyl optionally containing one or two heteroatoms, (C _2-6 ) alkenyl (all of which are optionally C _1-6 Alkyl or C _1-6 alkoxy, optionally substituted with NH ₂ , NH (Me) or N (ME) ₂ ),
e) NHR ¹¹² wherein R ¹¹² is aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, said aryl, Het, (C _1-6 alkyl) aryl or ( C _1-6 alkyl) Het is optionally substituted with R ¹⁵⁰ ),
j) COOH,
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) Aryl, and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
l) Phenyl or Het (both optionally substituted with R ¹⁵⁰ )
It may be substituted with 1-3 substituents selected from, preferably, R ^0.99 is
-1 or 2 substituents selected from halogen, NO ₂ , cyano or azide,
a) (C _1-6 ) alkyl or (C _2-6 ) alkenyl (both optionally substituted with COOH or CONH ₂ ),
b) OR ¹⁰⁴ (wherein R ¹⁰⁴ is H or (C _1-6 alkyl) optionally substituted with COOH),
h) NHCOCOOH,
j) COOH, and
k) CONH ₂
1 or 2 substituents selected from
Z is

Is preferably selected from.
Diamide:
Most preferably, R ⁶ is

Wherein preferably R ⁷ and R ⁸ are each independently H, (C _1-6 ) alkyl, haloalkyl, (C _3-7 ) cycloalkyl, 6- or 10-membered aryl, Het, (C _1-6 ) alkyl-aryl, (C _1-6 ) alkyl-Het, the alkyl, cycloalkyl, aryl, Het, (C _1-6 ) alkyl-aryl, (C _1-6 ) alkyl-Het are Optionally substituted with R ⁷⁰ , or
R ⁷ and R ⁸ are covalently bonded together to form a 4-membered, 5-membered or 6-membered (C _3-7 ) cycloalkyl or 1-3 heteroatoms selected from O, N, and S Forms a membered heterocycle, or when Z is N (R ^6a ) R ⁶ , either R ⁷ or R ⁸ is covalently bonded to R ^6a to form a nitrogen-containing 5- or 6-membered heterocycle And
Preferably R ⁷⁰ is
1 to 4 substituents selected from halogen, NO ₂ , cyano, azide, or
a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, C _3-7 spirocycloalkyl optionally containing 1 or 2 heteroatoms, (C _2-6 ) Alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl (all of which may optionally be substituted with R ¹⁵⁰ ),
b) OR ^{104 wherein} R ¹⁰⁴ is H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, wherein the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is Optionally substituted with R ¹⁵⁰ ),

d) SR ¹⁰⁸ , SO ₂ N (R ¹⁰⁸ ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ¹⁰⁸ , wherein each R ¹⁰⁸ is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ^{108 of the above} are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6- or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het or heterocycle may be optionally substituted with R ¹⁵⁰ ),
e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ¹¹² is H, CN, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, COOR ¹¹⁵ or SO ₂ R ^{115 where} R ¹¹⁵ Is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or ( C _1-6 alkyl) Het), or both R ¹¹¹ and R ¹¹² are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-membered, 6-membered or 7-membered saturated complex. Forming a ring, said alkyl, cycloalkyl, aryl, Het, (C _1-6 Alkyl) aryl or (C _1-6 alkyl) Het, or a heterocycle optionally substituted with R ¹⁵⁰ ),
f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) Alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- ( C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹¹⁸ is covalently bound to R ¹¹⁹ and they are bound Bonded to nitrogen to form a 5-, 6-, or 7-membered saturated heterocycle, or ^R119 and ^R120 are covalently bonded together, and bonded to the nitrogen to which they are bonded, 5-membered, 6-membered Or a 7-membered saturated heterocycle, the alkyl, cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _{1- 6} alkyl) Het or heterocycle being optionally substituted with R ^0.99 if necessary),

h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, 6 Membered or 10 membered aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) Aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ and R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ , wherein R ¹²³ and each R ¹²⁴ is Independently H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) Aryl or (C _1-6 alkyl) Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), or both R ¹²⁴ are covalently bonded together to be 5, 6 or 7 members. Forming a saturated heterocycle, said alkyl, cyclo Alkyl, alkyl - cycloalkyl, aryl, Het, optionally substituted with (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het and R ^0.99 by heterocycle necessary),
i) COR ^{127 wherein} R ¹²⁷ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het , (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is necessary ^Optionally substituted by R ¹⁵⁰ )
j) COOR ^{128 wherein} R ¹²⁸ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het , (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),

k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ¹²⁹ and R ¹³⁰ are covalently bonded together and they are bonded Combined with nitrogen to form a 5-, 6- or 7-membered saturated heterocycle, the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁵⁰ ),
l) Aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het (all of which may optionally be substituted with R ¹⁵⁰ )
Selected from 1 to 4 substituents, preferably R ¹⁵⁰ is
- halogen, NO _2, cyano, 1 to 3 substituents selected from azido, or
a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, C _3-7 spirocycloalkyl optionally containing 1 or 2 heteroatoms, (C _2-6 ) Alkenyl, (C _2-8 ) alkynyl (all of which may optionally be substituted with R ¹⁶⁰ ),
b) OR ¹⁰⁴ (wherein R ¹⁰⁴ is H, (C _1-6 alkyl) or (C _3-7 ) cycloalkyl, and the alkyl and cycloalkyl may be optionally substituted with R ¹⁶⁰ ) ,
d) SR ¹⁰⁸ , SO ₂ N (R ¹⁰⁸ ) ₂ (wherein R ¹⁰⁸ is H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl, and the alkyl or cycloalkyl is R if necessary) ¹⁶⁰ may be substituted)
e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl, and R ¹¹² is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, COOR ¹¹⁵ or SO ₂ R ¹¹⁵ (wherein R ¹¹⁵ is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, ( C _1-6 alkyl) aryl or (C _1-6 alkyl) Het), or both R ¹¹¹ and R ¹¹² are covalently bonded together and bonded to the nitrogen to which they are bonded. Forms a 6-membered, 6-membered or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or a heterocycle optionally R ¹⁶⁰ May be substituted)
f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl, and the (C _1-6 ) alkyl or (C _{3 -7} ) cycloalkyl may be optionally substituted with R ¹⁶⁰ ),

g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are each H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl, or R ¹¹⁹ and R ¹²⁰ are Are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6- or 7-membered saturated heterocycle, said alkyl, cycloalkyl or heterocycle optionally substituted with R ¹⁶⁰ You may)
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ is H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl, and the alkyl or cycloalkyl may be optionally substituted with R ¹⁶⁰ Well, or R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ , wherein R ¹²³ and each R ¹²⁴ is independently H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl. Or R ¹²⁴ is OH or O (C _1-6 alkyl), or both R ¹²⁴ are covalently bonded together to form a 5-, 6- or 7-membered saturated heterocycle, said alkyl, cyclo Alkyl and heterocycle may be optionally substituted with R ¹⁶⁰ ),
j) Tetrazole, COOR ¹²⁸ (wherein R ¹²⁸ is H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl, and said (C _1-6 ) alkyl and (C _3-7 ) cyclo Alkyl may be optionally substituted with R ¹⁶⁰ ), and
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl, or both R ¹²⁹ and R ¹³⁰ together Covalently bonded to the nitrogen to which they are attached to form a 5-, 6- or 7-membered saturated heterocycle, wherein the alkyl, cycloalkyl and heterocycle may be optionally substituted with R ¹⁶⁰ Good),
Selected from 1 to 3 substituents selected from
R ¹⁶⁰ is defined as one or two substituents selected from tetrazole, halogen, CN, C _1-6 alkyl, haloalkyl, COOR ¹⁶¹ , OR ¹⁶¹ , N (R ¹⁶² ) ₂ or CON (R ¹⁶² ) ₂ In which R ¹⁶¹ and each R ¹⁶² is independently H or (C _1-6 ) alkyl.

More preferably, R ⁷ and R ⁸ are each independently H, (C _1-6 ) alkyl, haloalkyl, (C _3-7 ) cycloalkyl, 6- or 10-membered aryl, Het, (C _1-6 ) alkyl. -Aryl, (C _1-6 ) alkyl-Het, all of which are optionally halogen or
a) (C _1-6 ) alkyl, and
b) N (R ^{8a ′} ) ₂ , COR ^8a , or SO ₂ R ^{8a ”} , COOR ^8a , COCOOR ^8a , CON (R ^{8a ′} ) ₂ , COCON (R ^{8a ′} ) ₂ (wherein each R ^8a or R ^{8a ′} is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, or each R ^{8a 'Are} independently covalently bonded together and bonded to the nitrogen to which they are both bonded to form a 5-, 6-, or 7-membered saturated heterocycle, or R ^{8a "} is independently (C _{1- 6} ) Alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl)
Optionally substituted with 1 to 4 substituents selected from
4-membered, 5-membered or 6-membered heterocycle having 1-3 heteroatoms selected from (C _3-7 ) cycloalkyl, O, N, and S, wherein R ⁷ and R ⁸ are covalently bonded together Form.
Most preferably, R ⁷ and R ⁸ are each independently H, (C _1-6 ) alkyl, haloalkyl, (C _3-7 ) cycloalkyl, 6- or 10-membered aryl, Het, (C _1-6 ) alkyl. -Aryl, (C _1-6 ) alkyl-Het, or R ⁷ and R ⁸ are covalently bonded together to form cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidine, piperidine, tetrahydrofuran, tetrahydropyran, or pentamethylene sulfide And
The alkyl, haloalkyl, (C _3-7 ) cycloalkyl, 6- or 10-membered aryl, Het, (C _1-6 ) alkyl-aryl, (C _1-6 ) alkyl-Het, cyclopropyl, cyclobutyl, cyclopentyl, If necessary, pyrrolidine, piperidine, tetrahydrofuran, tetrahydropyran, or pentamethylene sulfide
a) (C _1-6 ) alkyl, and
_{b) NH 2, N (CH} 2 CH) 2, COCH 3, or SO ₂ CH ₃
It may be monosubstituted with a substituent selected from
More preferably, R ⁷ and R ⁸ are

Chosen from.
R ⁷ and R ⁸ together

Form.
Most preferably, R ⁷ and R ⁸ are

Selected from the group consisting of
R ⁹ :
Preferably, R ⁹ is H, or R ⁹ is covalently bonded to either R ⁷ or R ⁸ to form a 5 or 6 membered heterocycle. More preferably, R ⁹ is H.
Q:
Preferably Q is 6- or 10-membered aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) -Het, all of which are optionally

May be replaced with
R ¹⁰⁰
- halogen, NO _2, 1 to 4 substituents selected from cyano or azido, or
a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, (C _2-6 ) alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl (all of which may optionally be substituted with R ¹⁵⁰ ),
b) OR ^{104 wherein} R ¹⁰⁴ is H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, wherein the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is Optionally substituted with R ¹⁵⁰ ),
d) SR ^{108 wherein} R ¹⁰⁸ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het , (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, all of which may be optionally substituted with R ¹⁵⁰ ),
e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ¹¹² is H, CN, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, COOR ¹¹⁵ or SO ₂ R ^{115 where} R ¹¹⁵ Is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or ( C _1-6 alkyl) Het), or both R ¹¹¹ and R ¹¹² are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-membered, 6-membered or 7-membered saturated complex. Forming a ring, said alkyl, cycloalkyl, aryl, Het, (C _1-6 Alkyl) aryl or (C _1-6 alkyl) Het, or a heterocycle optionally substituted with R ¹⁵⁰ ),

f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) Alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- ( C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹¹⁸ is covalently bound to R ¹¹⁹ and they are bound Bonded to nitrogen to form a 5-, 6-, or 7-membered saturated heterocycle, or ^R119 and ^R120 are covalently bonded together, and bonded to the nitrogen to which they are bonded, 5-membered, 6-membered Or a 7-membered saturated heterocycle, the alkyl, cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _{1- 6} alkyl) Het or heterocycle being optionally substituted with R ^0.99 if necessary),
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ and R ¹²² are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ), respectively. Cycloalkyl, 6- or 10-membered aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het is optionally substituted with R ¹⁵⁰ , or R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ , wherein R ¹²³ and each R ¹²⁴ is independently H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), or both R ¹²⁴ are covalently bonded together to form a 5-membered, 6 Forming a 7-membered or 7-membered saturated heterocyclic ring, Alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het and heterocycle optionally substituted with R ¹⁵⁰ ),

j) COOR ^{128 wherein} R ¹²⁸ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het , (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ¹²⁹ and R ¹³⁰ are covalently bonded together and they are bonded Combined with nitrogen to form a 5-, 6- or 7-membered saturated heterocycle, the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁵⁰ ),
l) Aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het (all of which may optionally be substituted with R ¹⁵⁰ )
1 to 4 substituents selected from: R ¹⁵⁰ is
1 to 3 substituents selected from halogen, NO ₂ , cyano or azide, or
a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, C _3-7 spirocycloalkyl optionally containing 1 or 2 heteroatoms, (C _2-6 ) Alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl (all of which may optionally be substituted with R ¹⁶⁰ ),
b) OR ^{104 wherein} R ¹⁰⁴ is H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, wherein the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is Optionally substituted with R ¹⁶⁰ ),

d) SR ¹⁰⁸ , SO ₂ N (R ¹⁰⁸ ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ¹⁰⁸ , wherein each R ¹⁰⁸ is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ^{108 of the above} are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6- or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het or heterocycle being optionally substituted with R ¹⁶⁰ as required),
e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ¹¹² is H, CN, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het or SO ₂ R ^{115 where} R ¹¹⁵ is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _{1- 6} alkyl) Het), or both R ¹¹¹ and R ¹¹² are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6-, or 7-membered saturated heterocycle and said alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) Reel or (C _1-6 alkyl) Het, or heterocycle being optionally substituted with R ¹⁶⁰ as required),
f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) Alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁶⁰ ),

g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- ( C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹¹⁸ is covalently bound to R ¹¹⁹ and they are bound Bonded to nitrogen to form a 5-, 6-, or 7-membered saturated heterocycle, or ^R119 and ^R120 are covalently bonded together and bonded to the nitrogen to which they are bonded, 5-membered, 6-membered Or a 7-membered saturated heterocyclic ring, and the alkyl, cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _{1- 6} alkyl) Het or heterocycle being optionally substituted with R ¹⁶⁰ as required),
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ is H, (C _1-6 ) alkyl optionally substituted with R ¹⁶⁰ , and R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ Wherein R ¹²³ and each R ¹²⁴ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cyclo Alkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), or both R ¹²⁴ are together To form a 5-membered, 6-membered or 7-membered saturated heterocyclic ring, and the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁶⁰ ),
j) Tetrazole, COOR ¹²⁸ (wherein R ¹²⁸ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl) , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁶⁰ ), and
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ¹²⁹ and R ¹³⁰ are covalently bonded together and they are bonded Combined with nitrogen to form a 5-, 6- or 7-membered saturated heterocycle, the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁶⁰ ),
Selected from 1 to 3 substituents selected from
R ¹⁶⁰ is tetrazole, halogen, CN, C _1-6 alkyl, haloalkyl, COOR ¹⁶¹ , SO ₃ H, SR ¹⁶¹ , SO ₂ R ¹⁶¹ , OR ¹⁶¹ , N (R ¹⁶² ) ₂ , SO ₂ N (R ¹⁶² ) ₂ , NR ¹⁶² COR ¹⁶² or CON (R ¹⁶² ) ₂ defined as one or two substituents, wherein R ¹⁶¹ and each R ¹⁶² are independently H, (C _1-6 ) alkyl , (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, or both R ¹⁶² are covalently bonded together and the nitrogen to which they are bonded To form a 5-, 6-, or 7-membered saturated heterocyclic ring.

More preferably, Q is 6- or 10-membered aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) -Het, all of which are optionally
- halogen, NO _2, 1 to 4 substituents selected from cyano or azido, or
a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, (C _2-6 ) alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl (all of which may optionally be substituted with R ¹⁵⁰ ),
b) OR ^{104 wherein} R ¹⁰⁴ is H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, wherein the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is Optionally substituted with R ¹⁵⁰ ),
d) SR ¹⁰⁸ , SO ₂ N (R ¹⁰⁸ ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ¹⁰⁸ , wherein each R ¹⁰⁸ is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ^{108 of the above} are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6- or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het or heterocycle may be optionally substituted with R ¹⁵⁰ ),
e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ¹¹² is H, CN, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, COOR ¹¹⁵ or SO ₂ R ^{115 where} R ¹¹⁵ Is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or ( C _1-6 alkyl) Het), or both R ¹¹¹ and R ¹¹² are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-membered, 6-membered or 7-membered saturated complex. Forming a ring, said alkyl, cycloalkyl, aryl, Het, (C _1-6 Alkyl) aryl or (C _1-6 alkyl) Het, or a heterocycle optionally substituted with R ¹⁵⁰ ),

f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) Alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- ( C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹¹⁹ and R ¹²⁰ are covalently bonded together and they are bonded To form a 5-membered, 6-membered or 7-membered saturated heterocyclic ring, and the alkyl, cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, ( C _1-6 alkyl) aryl or (C _1-6 alkyl) Het or heterocycle may be optionally substituted with R ¹⁵⁰ ),
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ is H, (C _1-6 ) alkyl optionally substituted with R ¹⁵⁰ and R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ Wherein R ¹²³ and each R ¹²⁴ are independently H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cyclo Alkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), or both R ¹²⁴ are together To form a 5-membered, 6-membered or 7-membered saturated heterocyclic ring, and the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁵⁰ ),

j) COOR ^{128 wherein} R ¹²⁸ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het , (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ¹²⁹ and R ¹³⁰ are covalently bonded together and they are bonded Combined with nitrogen to form a 5-, 6- or 7-membered saturated heterocycle, the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁵⁰ ),
l) Aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het (all of which may optionally be substituted with R ¹⁵⁰ )
Optionally substituted with 1 to 4 substituents selected from: R ¹⁵⁰ is preferably
1 to 3 substituents selected from halogen, NO ₂ , cyano or azide, or

a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, (C _2-6 ) alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl (all of which may optionally be substituted with R ¹⁶⁰ ),
b) OR ^{104 wherein} R ¹⁰⁴ is H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, wherein the alkyl, cycloalkyl, aryl and Het are optionally substituted with R ¹⁶⁰ ),
c) OCOR ^{105 wherein} R ¹⁰⁵ is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het, the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is optionally in R ¹⁶⁰ May be substituted),
d) SR ¹⁰⁸ , SO ₂ N (R ¹⁰⁸ ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ¹⁰⁸ , wherein each R ¹⁰⁸ is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or both R ¹⁰⁸ are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6-, or 7-membered saturated heterocycle, the alkyl , A cycloalkyl or heterocycle may be optionally substituted with R ¹⁶⁰ ),
e) NR ¹¹¹ R ^{112 where} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl. And R ¹¹² is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, COOR ¹¹⁵ or SO ₂ R ¹¹⁵ (formula R ¹¹⁵ is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl), or both R ¹¹¹ and R ¹¹² are covalently bonded together and the nitrogen to which they are bonded To form a 5-membered, 6-membered or 7-membered saturated heterocyclic ring, the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or heterocyclic ring ^{May be} optionally substituted with R ¹⁶⁰ )
f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) Alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁶⁰ ),

g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are each H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or R ¹¹⁹ and R ¹²⁰ are Are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6- or 7-membered saturated heterocycle, said alkyl, cycloalkyl or heterocycle optionally substituted with R ¹⁶⁰ You may)
h) NR ¹²¹ COCOR ^{122 where} R ¹²¹ is H, (C _1-6 ) alkyl optionally substituted with R ¹⁶⁰ , or R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ In which R ¹²³ and each R ¹²⁴ are independently H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl, or R ¹²⁴ is OH or O (C _1-6 alkyl) Or both R ¹²⁴ may be covalently bonded together to form a 5-, 6- or 7-membered saturated heterocycle, wherein the alkyl, cycloalkyl and heterocycle may be optionally substituted with R ^160. ),
j) Tetrazole, COOR ¹²⁸ (wherein R ¹²⁸ is H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl, and said (C _1-6 ) alkyl and (C _3-7 ) cyclo Alkyl may be optionally substituted with R ¹⁶⁰ ), and
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl, or both R ¹²⁹ and R ¹³⁰ together Covalently bonded to the nitrogen to which they are attached to form a 5-, 6- or 7-membered saturated heterocycle, wherein the alkyl, cycloalkyl and heterocycle may be optionally substituted with R ¹⁶⁰ Good),
Selected from 1 to 3 substituents selected from
R ¹⁶⁰ is tetrazole, halogen, CN, C _1-6 alkyl, haloalkyl, COOR ¹⁶¹ , SO ₃ H, SO ₂ R ¹⁶¹ , OR ¹⁶¹ , N (R ¹⁶² ) ₂ , SO ₂ N (R ¹⁶² ) ₂ , NR ¹⁶² Defined as one or two substituents selected from COR ¹⁶² or CON (R ¹⁶² ) ₂ , wherein R ¹⁶¹ and each R ¹⁶² are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, or both R ¹⁶² are covalently bonded together and bound to the nitrogen to which they are bound. Form a 5-, 6- or 7-membered saturated heterocycle.

Most preferably, Q is 6- or 10-membered aryl or Het, both of which are optionally
-1～3 halogen, NO _2, cyano, azido, or
a) primary (C _1-6 ) alkyl or haloalkyl, primary (C _3-7 ) cycloalkyl, (C _2-6 ) alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl -(C _3-7 ) cycloalkyl (all of which may optionally be substituted with R ¹⁵⁰ ),
b) OR ^{104 where} R ¹⁰⁴ is H, (C _1-6 alkyl),
d) SO ₂ NHR ^{108 where} R ¹⁰⁸ is H or (C _1-6 ) alkyl.
e) NR ¹¹¹ R ¹¹² where both R ¹¹¹ and R ¹¹² are independently H or (C _1-6 ) alkyl.
f) NHCOR ¹¹⁷ (wherein R ¹¹⁷ is H or (C _1-6 ) alkyl),
g) NHCONR ¹¹⁹ R ^{120 where} R ¹¹⁹ and R ¹²⁰ are each independently H or (C _1-6 ) alkyl.
h) NHCOCOR ^{122 where} R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ , wherein R ¹²³ and each R ¹²⁴ is independently H or (C _1-6 alkyl)),
j) COOR ¹²⁸ (wherein R ¹²⁸ is H, (C _1-6 ) alkyl),
k) CONHR ¹³⁰ (wherein R ¹³⁰ is H, (C _1-6 ) alkyl),
l) 6- or 10-membered aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het (said aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ )
May be substituted with 1 to 3 substituents selected from

Preferably R ¹⁵⁰ is
-1 to 3 halogens, or
a) primary (C _1-6 ) alkyl or haloalkyl, primary (C _3-7 ) cycloalkyl, (C _2-6 ) alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl -(C _3-7 ) cycloalkyl (all of which may optionally be substituted with tetrazole, OR ¹⁰² , COOR ¹⁰² , where R ¹⁰² is H or (C _1-6 ) alkyl) ,
b) OR ^{104 where} R ¹⁰⁴ is H, (C _1-6 alkyl),
d) SO ₂ NHR ^{108 where} R ¹⁰⁸ is H or (C _1-6 ) alkyl.
e) NR ¹¹¹ R ¹¹² where both R ¹¹¹ and R ¹¹² are independently H or (C _1-6 ) alkyl.
f) NHCOR ^{117 where} R ¹¹⁷ is H or (C _1-6 ) alkyl; and
h) NHCOCOR ^{122 where} R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ , wherein R ¹²³ and each R ¹²⁴ is independently H or (C _1-6 alkyl)),
j) COOR ^{128 where} R ¹²⁸ is H, (C _1-6 ) alkyl, and
k) CONHR ¹³⁰ (wherein R ¹³⁰ is H, (C _1-6 ) alkyl)
Selected from 1 to 3 substituents.
Q is

More preferably, it is chosen from.
Q is

Most preferably, it is selected from
Particular embodiments included within the scope of the invention are all compounds of formula I shown in Tables 1-9.
Polymerase activity
The ability of the compound of formula (I) to inhibit RNA synthesis by HCV RNA-dependent RNA polymerase can be demonstrated by any assay that can measure RNA-dependent RNA polymerase activity. Suitable assays are described in the examples.
Specificity for RNA-dependent RNA polymerase activity To demonstrate that the compounds of the invention act by specific inhibition of HCV polymerase, the compounds can be tested for inhibitory activity in a DNA-dependent RNA polymerase assay.
When a compound of formula (I), or one of its therapeutically acceptable salts, is used as an antiviral agent, it is used in mammals such as humans, rabbits or mice in a vehicle containing one or more pharmaceutically acceptable carriers. Orally, topically or systemically administered, the ratio being determined by the solubility and chemical nature of the compound, the route of administration chosen and the usual biological practices.
For oral administration, the compound or a therapeutically acceptable salt thereof is in unit dosage form, eg, capsules or tablets each containing a predetermined amount of the active ingredient, each in the range of about 25-500 mg in a pharmaceutically acceptable carrier. Can be formulated.
For topical administration, the compounds may be formulated in a pharmaceutically acceptable vehicle containing 0.1-5%, preferably 0.5-5%, of the active ingredient. Such formulations may be in the form of a solution, cream or lotion.
For parenteral administration, the compound of formula (I) is administered by intravenous, subcutaneous or intramuscular injection in a composition comprising a pharmaceutically acceptable vehicle or carrier. For administration by injection and other solutes such as buffers or preservatives, solutions in sterile aqueous vehicles that may contain a sufficient amount of pharmaceutically acceptable salt or glucose to make the solution isotonic It is preferred to use the compounds in

Suitable vehicles or carriers for such formulations are pharmaceutical books such as “Remington's Pharmaceutical Sciences and Practices”, Volume 19, Mack Publishing Company, Easton, Penn., 1995, or “Pharmaceutical Dosage Forms and Drug Delivery Systems”. 6th edition, edited by HC Ansel et al., Williams & Wilkins, Baltimore, Maryland, 1995.
The dose of the compound will vary with the chosen mode of administration and the particular active ingredient. Furthermore, it will vary with the particular host being treated. In general, treatment is initiated in small increments until the optimum effect under the circumstances is reached. In general, it is most desirable that the compounds of Formula I be administered at a concentration level that will generally produce effective antiviral results without causing adverse or dangerous side effects.
For oral administration, the compound or therapeutically acceptable salt is administered daily in the range of 10-200 mg / kg body weight, preferably in the range of 25-150 mg / kg.
For systemic administration, the compound of formula (I) is administered daily at a dose of 10 mg to 150 mg / kg body weight, but the above changes will occur. Most preferably, dosage levels in the range of about 10 mg to 100 mg per kg body weight daily are used to obtain effective results.
When a composition of the invention comprises a combination of a compound of formula I and one or more additional therapeutic or prophylactic agents, about 10 doses of the compound and additional agent both normally administered in a monotherapy regimen. It should be present at a dose level of -100%, more preferably about 10-80%.
When these compounds or their pharmaceutically acceptable salts are formulated together with a pharmaceutically acceptable carrier, the resulting composition inhibits HCV polymerase or humans to treat or prevent HCV viral infections Can be administered in vivo to such mammals. Such treatments also include drugs (immunomodulators such as α-, β-, or γ-interferons; other antiviral agents such as ribavirin, amantadine; other inhibitors of HCV NS5B polymerase; other in the HCV life cycle Inhibitors of the target of (including but not limited to helicase, NS2 / 3 protease, NS3 protease, or internal ribosome entry site (IRES)); or combinations thereof May be obtained using the compounds of the present invention. Additional agents may be combined with the compounds of the present invention to produce a single dosage form. These additional agents may also be administered separately to the mammal as part of a multiple dosage form.

Methods and Synthesis The indole derivatives or analogs of the present invention are known as described by JW Ellingboe et al. (Tet. Lett. 1997, 38, 7963) and S. Cacchi et al. (Tet. Lett. 1992, 33, 3915). It can be prepared from known monocyclic aromatic compounds by adapting the literature order. Scheme 1 shown below (wherein R ¹ , R ² , R ³ , R ⁶ , K, L, and M are as described herein) is the operation of these compounds in formula 1 of the present invention. The method which can be suitable for the synthesis | combination of this compound is shown.
Scheme 1

In carrying out the route shown in Scheme 1, a suitably protected form I (i) of 3-trifluoroacetamido-4-iodobenzoic acid is converted to a metal catalyst (eg, a palladium metal complex such as PdCl ₂ (PPh ₃ ) ₂ , Pd ₂ dba ₃ , Pd (PPh ₃ ) ₄ etc.), base (Et ₃ N, DIEA etc., or inorganic basic salts including metal carbonates, fluorides and phosphates) To react with alkyne I (ii) in the presence of additional phosphine ligands (triaryl or heteroarylphosphine, dppe, dppf, dppp, etc.). Suitable solvents for this reaction include DMF, dioxane, THF, DME, toluene, MeCN, DMA, etc., at temperatures ranging from 20 ° C. to 170 ° C., or heating the components together without the use of a solvent. May be performed. Alternatively, the cross-coupling reaction can be performed on a suitably protected form of 3-amino-4-iodobenzoate where the amino group is as described by JW Ellingboe et al. (Tet. Lett. 1997, 38, 7963). Subsequent steps can be trifluoroacetylated. The diarylalkyne I (iii) is reacted with enol triflate under cross-coupling conditions similar to those described above to give the indole derivative I (iv) after hydrogenation of the double bond. Enol triflate is known and can be prepared from the corresponding ketone by following known literature methods (eg, cyclohexan triflate is cyclohexanone, triflic anhydride and hindered organic bases such as 2,6-di-tert- May be prepared from butyl-4-methylpyridine). Hydrogenation of the double bond initially present in R ¹ is performed by hydrogen gas or hydrogen donor (ammonium formate, formic acid) in the presence of a metal catalyst (preferably Pd) in a suitable solvent (lower alkyl alcohol, THF, etc.). Etc.).
Finally, after hydrolysis of the ester protecting group in I (iv), the resulting 6-carboxyindole derivative I (v) is converted to the compound of formula 1 by coupling with the appropriate amine of formula H ₂ NR ⁶ To do. The condensation of the 6-indole carboxylic acid with amine H ₂ NR ⁶ can be accomplished using conventional amide bond forming reagents such as TBTU, HATU, BOP, BroP, EDAC, DCC, isobutyl chloroformate, etc., or with amines. Can be effected by activation of the carboxyl group by conversion to the corresponding acid chloride prior to condensation. After this step, the remaining protecting group is removed to give the compound of formula 1.
Also, the compound of formula 1 is amenable to literature manipulation as described, for example, by P. Gharagozloo et al. (Tetrahedron 1996, 52, 10185) or K. Freter (J. Org. Chem. 1975, 40, 2525). Can be prepared by finishing from existing indole cores. Such a method is shown in Scheme 2.
Scheme 2

In carrying out the route shown in Scheme 2, commercially available 6-indolecarboxylic acid 2 (i) (which can also be prepared according to the method of S. Kamiya et al. (Chem. Pharm. Bull. 1995, 43, 1692)) Is used as starting material. The indole 2 (i) is reacted with ketone 2 (ii) under basic or acidic aldol type conditions. Suitable conditions for carrying out this condensation are in solvents such as lower alkyl alcohols (MeOH, EtOH, tertBuOH, etc.), THF, dioxane, DMF, DMSO, DMA etc. at reaction temperatures ranging from -20 ° C to 120 ° C. Strong bases such as alkali metal hydroxides, alkoxides and hydrides. The condensation can also be carried out under acidic conditions using organic or inorganic acids or both. Suitable conditions include a mixture of AcOH and aqueous phosphoric acid at temperatures ranging from 15 ° C to 120 ° C.
After protection of the carboxylic acid in the form of an ester (usually lower alkyl) using known methods, the indole nitrogen can be optionally alkylated with R ³ . The reaction conditions for alkylating the nitrogen of the indole derivative are known to those skilled in the art and include suitable solvents (THF, dioxane, DME, DMF, MeCN, DMSO, alcohol, etc.) at temperatures ranging from -78 ° C to 140 ° C. ), And the use of alkali metal hydrides, hydroxides, amides, alkoxides and alkyl metals. The electrophilic form of R ³ is used for alkylation of indole anions. Such electrophilic species include iodide, bromide, chloride and sulfonate esters (mesylate, tosylate, brosylate or triflate). Halogenation at the 2-position of indole 2 (iv) (usually bromination or iodination) yields 2 (v). Suitable halogenating agents include, for example, elemental bromine, N-bromosuccinimide, pyridine tribromide, dibromohydantoin and the corresponding iodo derivatives. Suitable solvents for this reaction are inert to reactive halogenating agents such as hydrocarbons, chlorinated hydrocarbons (DCM, CCl ₄ , CHCl ₃ ), ethers (THF, DME, dioxane), acetic acid, ethyl acetate , IPA, and mixtures of these solvents. The reaction temperature ranges from -40 ° C to 100 ° C. A special method has been described by L. Chu (Tet. Lett. 1997, 38, 3871) for performing bromination of indoles as shown in Scheme 2.

The 2-bromoindole derivative 2 (v) can be directly converted to the fully substituted main intermediate I (v) by cross-coupling reaction with aryl or heteroaryl boronic acid, boronic ester or trialkyl stannate derivatives . These boron or tin organometallic species are from commercial sources or can be prepared by routine literature operations. Cross-coupling with organoboron reagents can be achieved by any change in the Suzuki cross-coupling reaction reported in the literature. This is usually a transition metal catalyst (usually Pd ⁰ ), a triaryl or triheteroaryl phosphine ligand, an additive such as an inorganic chloride (eg LiCl), and a base (usually an aqueous inorganic base such as sodium or potassium carbonate. Salt or phosphate). The reaction is usually carried out in an alcohol solvent (EtOH), DME, toluene, THF or the like at a temperature ranging from 25 ° C to 140 ° C.
Cross coupling with tin reagents can be achieved by any change in the still cross coupling reaction reported in the literature. This usually involves the use of transition metal catalysts (usually Pd ⁰ ), triaryl or triheteroaryl phosphine ligands, and additives such as inorganic chlorides (eg LiCl) or iodides (eg CuI). Suitable solvents for this reaction include toluene, DMF, THF, DME, etc. at temperatures ranging from 25 ° C to 140 ° C. Intermediate I (v) is then converted to a compound of formula 1 as described in Scheme 1.
Alternatively, 2-bromoindole intermediate 2 (v) can be exchange metallated to an organotin species (or organozinc) and can be used in a still-type cross-coupling reaction under the conditions described above. In this case, aromatic and heteroaromatic halides (chlorides, bromides, iodides) is or triflate are used to introduce R ^2. Conversion of the 2-bromoindole derivative 2 (v) to the corresponding organotin species 2 (vi) can be accomplished using an alkyllithium reagent (eg, nBuLi or tert-BuLi) or using lithium metal at an initial low temperature ( (Normally -78 ° C to -30 ° C) This is carried out by halogen-metal exchange. The temporary 2-lithioindole species is then captured with a trialkyltin halide (eg, nBu ₃ SnCl or Me ₃ SnCl). The lithioindole intermediate is also captured with zinc chloride to produce the corresponding organic zincate, which is also aromatic as described, for example, by M. Rowley (J. Med. Chem. 2001, 44, 1603). And can undergo transition metal catalyzed cross-coupling with heteroaromatic halides or triflates.
The present invention also includes compounds of formula 1 in which the carboxylic acid group is in the 5-position of the indole system. The synthesis of such compounds is shown in Scheme 3 based on the adaptation of literature operations.
Scheme 3

In carrying out the synthetic route shown in Scheme 3, ethyl 4-acetamido-3-iodobenzoate 3 (i) is alkyne according to the adaptation of the procedure described by A. Bedeschi et al. (Tet. Lett. 1997, 38, 2307). Subject to metal-catalyzed cross-coupling with 3 (ii) to give 2,3-disubstituted-5-indolecarboxylate 3 (iii). The indole derivative 3 (iii) is then converted to an electrophilic R ¹ group at the nitrogen position under the action of a base such as an alkali metal hydroxide, fluoride, hydride, amide, alkyllithium, phosphorus base, etc. Alkylation with halide, sulfonate ester) to give 3 (iv). Suitable solvents for this alkylation include DMF, DMA, DMSO, MeCN, THF, dioxane, DME and the like. After saponification of the ester group with an alkaline solution, the resulting 5-indolecarboxylic acid derivative 3 (v) is coupled to H ₂ NR ⁶ using an amide bond forming reagent as previously described (Scheme 1). To obtain a compound of formula I.

The invention is further illustrated by the following non-limiting examples. All reactions were performed in a nitrogen or argon atmosphere. The temperature is given in ° C. Flash chromatography was performed on silica gel. Solution% or ratio expresses a volume to volume relationship unless otherwise stated. Mass spectral analysis was recorded using electrospray mass spectrometry. The following are mentioned as abbreviations or symbols used here.
DIEA: diisopropylethylamine;
DMAP: 4- (dimethylamino) pyridine;
DMSO: dimethyl sulfoxide;
DMF: N, N-dimethylformamide;
Et: ethyl;
EtOAc: ethyl acetate;
Et ₂ O: diethyl ether;
HPLC: high performance liquid chromatography;
ⁱ Pr: isopropyl;
Me: methyl;
MeOH: methanol;
MeCN: acetonitrile;
Ph: phenyl;
TBE: Tris-Borate-EDTA;
TBTU: 2- (1H-benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium tetrafluoroborate;
TFA: trifluoroacetic acid;
TFAA: trifluoroacetic anhydride;
THF: tetrahydrofuran;
MS (ES): Electrospray mass spectrometry;
PFU: plaque forming unit;
DEPC: diethyl pyrocarbonate;
DTT: Dithiothreitol;
EDTA: ethylenediaminetetraacetic acid;
HATU: O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate;
BOP: benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate;

EDAC: See ECD;
DCC: 1,3-dicyclohexylcarbodiimide;
HOBt: 1-hydroxybenzotriazole;
ES ⁺ : Electrospray (positive ionization);
ES ^-: electrospray (negative ionization);
DCM: dichloromethane;
TBME: tert-butyl methyl ether;
TLC: thin layer chromatography;
AcOH: acetic acid;
EtOH: ethanol;
DBU: 1,8-diazabicyclo [5.4.0] undec-7-ene;
BOC: tert-butyloxycarbonyl;
Cbz: carbobenzyloxycarbonyl;
ⁱ PrOH: isopropanol;
NMP: N-methylpyrrolidone;
EDC: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride;
RNAsin: a ribonuclease inhibitor marketed by Promega;
Tris: 2-amino-2-hydroxymethyl-1,3-propanediol;
UMP: uridine 5'-monophosphate;
UTP: uridine 5'-triphosphate;
IPA: Isopropyl Acetate Example 1-45 shows a method for the synthesis of representative compounds of the invention.
Example 1

Methyl 3-amino-4-iodobenzoate:
3-Amino-4-iodobenzoic acid (13.35 g, 50.8 mmol) was added to MeOH (150 ml) and SOCl ₂ (4.8 ml, 65.8 mmol, 1.3 eq) was added. The mixture was refluxed for 3 hours and then the volatiles were removed under reduced pressure. The residue was coevaporated 3 times with MeOH and dried in vacuo (15.23 g).
Methyl 3-trifluoroacetamido-4-iodobenzoate:
The previous aniline derivative (14.53 g, 52 mmol) was dissolved in DCM (200 ml) and TFAA (15 ml, 104 mmol) was added. The dark purple solution was refluxed overnight. Volatiles were removed under reduced pressure and the residue was passed through a short pad of silica gel using DCM as the eluent. The desired product was obtained as a pink solid (13.81 g).
4-Phenylethynyl-3- (2,2,2-trifluoro-ethanoylamino) -benzoic acid methyl ester:
The previous iodide (0.742 g, 2 mmol), phenylacetylene (0.37 ml, 3.9 mmol, 1.7 eq) and Et ₃ N (6 ml) were charged into a dry flask under an argon atmosphere. PdCl ₂ (PPh ₃ ) ₂ (0.241 g, 0.3 mmol) was added and the mixture was stirred at room temperature until judged complete by HPLC analysis (about 5 hours). The reaction mixture was concentrated under reduced pressure to half volume and diluted with water (80 ml). The mixture was extracted with EtOAc (3 × 100 ml) and the organic extract was washed with 5% HCl (100 ml) followed by (100 ml) and brine (40 ml). After drying over MgSO ₄ , the residue was purified by flash chromatography using 20% EtOAc-hexane as eluent to give the desired cross-coupled alkyne as a tan solid (0.442 g).
Methyl 3- (cyclohexenyl) -2-phenylindole 6-carboxylate:
A flame-dried flask was charged with finely powdered anhydrous K ₂ CO ₃ (0.153 g, 1.1 mmol) and the above alkyne derivative (0.390 g, 1.1 mmol). Dry DMF (4 ml) was added and the suspension was degassed with a stream of argon. Enol triflate derived from cyclohexanone (0.802 g, prepared according to the procedure described by AG Martinez, M. Hanack et al. (J. Heterocyclic Chem. 1988, 25, 1237) or equivalent methods described therein. 3.3 mmol, 3 eq) was added followed by Pd (PPh ₃ ) ₄ (0.086 g, 0.07 mmol) and the mixture was stirred at room temperature for 8 hours. DMF was removed in vacuo and the residue was purified by flash chromatography using DCM as eluent (0.260 g).
Methyl 3-cyclohexyl-2-phenylindole-6-carboxylate:
The previous material was hydrogenated with 20% Pd (OH) ₂ in the usual manner (1 atm H ₂ gas) using MeOH as the solvent. The desired cyclohexaneindole was isolated after filtration of the catalyst.
3-cyclohexyl-2-phenylindole-6-carboxylic acid:
The previous methyl ester (0.154 g, 0.15 mmol) was refluxed in a mixture of MeOH (10 ml) and 2N NaOH (6 ml) overnight until complete hydrolysis occurred as shown by HPLC analysis. After cooling to room temperature, 2N HCl (5 ml) was added followed by AcOH until pH 7. MeOH was removed under reduced pressure, water (50 ml) was added and the product was extracted with EtOAc. The extract was washed with water and brine and dried (MgSO ₄ ). Volatiles were removed under reduced pressure to give the title indole carboxylic acid as a light orange solid (0.149 g).
3-Cyclohexane-2- (2-pyridyl) indole-6-carboxylic acid was obtained following the same procedure except that 2-ethynylpyridine was used instead of phenylacetylene.
Example 2:

3-Cyclohexanyl-6-indolecarboxylic acid:
A 12 L round bottom flask was equipped with a reflux condenser and a mechanical stirrer and the system was purged with nitrogen gas. 6-indolecarboxylic acid (300.00 g, 1.86 mol, 3 eq) was charged to the flask followed by MeOH (5.5 L). After stirring at room temperature for 10 minutes, cyclohexanone (579 ml, 5.58 mol) was added. Methanolic sodium methoxide (25% w / w, 2.6 L, 11.37 mol, 6.1 eq) was added in portions over 10 minutes. The mixture was then refluxed for 48 hours. After cooling to room temperature, water (4 L) was added and methanol was removed under reduced pressure. The residual aqueous phase was acidified to pH 1 with concentrated HCl (about 1.2 L). The resulting yellow precipitate was collected by filtration, washed with water and dried at 50 ° C. under reduced pressure. The desired cyclohexane derivative was obtained as a beige solid (451.0 g, 100% yield).
3-Cyclohexyl-6-indolecarboxylic acid:
Using 1: 1 THF-MeOH (2.5 L) as the solvent, the previous unsaturated derivative was converted to 20% Pd (OH) ₂ / C over 20 hours at 55 psi (3.9 kg / cm ² ) hydrogen gas pressure. Hydrogenated with (10.25 g). After filtration of the catalyst, volatiles were removed under reduced pressure and the residue was triturated with hexane. A beige solid was collected by filtration, washed with hexane and dried in vacuo (356.4 g, 78% yield).
Methyl 3-cyclohexyl-6-indolecarboxylate:
A 5 L 3-neck flask was equipped with a reflux condenser and a mechanical stirrer, and the system was purged with nitrogen gas. The previous indole carboxylic acid (300.00 g, 1.233 mol) was charged to the flask and suspended in MeOH (2 L). Thionyl chloride (5 ml, 0.0685 mol, 0.05 eq) was added dropwise and the mixture was refluxed for 48 hours. Volatiles were removed under reduced pressure and the residue was triturated with hexane to give a beige solid that was washed with hexane and dried in vacuo (279.6 g, 88% yield).
Methyl-2-bromo-3-cyclohexyl-6-indolecarboxylate:
Adapting the procedure of L. Chu (Tet. Lett. 1997, 38, 3871), methyl 3-cyclohexyl-6-indolecarboxylate (4.65 g, 18.07 mmol) was added to THF (80 ml) and CHCl ₃ (80 ml). Dissolved in the mixture. The solution was cooled in an ice bath and pyridinium bromide perbromide (pyridine tribromide, 7.22 g, 22.6 mmol, 1.25 eq) was added. After stirring at 0 ° C. for 1.5 hours, the reaction was judged complete by TLC. It was diluted with CHCl ₃ (200 ml) and washed with 1M NaHSO ₃ (2 × 50 ml), saturated aqueous NaHCO ₃ solution (2 × 50 ml) and brine (50 ml). After drying over Na ₂ SO _4, the solvent was removed in vacuo and the residue was crystallized with TBME- hexane. The desired 2-bromoindole derivative was collected by filtration, washed with hexane and dried (3.45 g). The mother liquor was evaporated to give a red solid that was purified by flash chromatography using 15% EtOAc in hexanes to give an additional 3.62 g of pure material. The total yield was 5.17 g (85% yield).

Example 3:
General procedure for Suzuki cross-coupling of aryl and heteroaryl boronic acids with 2-bromoindole derivatives
Cross-coupling of aromatic / heteroaromatic boronic acid or ester derivatives with 2-bromoindoles, such as those described in Example 2, is described in the literature and is conventional metal catalyzed Suzuki crossover known to those skilled in the art. Any change in the coupling reaction can be used. The following examples can be used to illustrate such a method and are non-limiting.
3-cyclohexyl-2-furan-3-yl-1H-indole-6-carboxylic acid methyl ester:

2-bromoindole of Example 2 (8.92 g, 26.5 mmol), 3-furanboronic acid (BP Roques et al., J. Heterocycl. Chem. 1975, 12, 195; 4.45 g, 39.79 mmol, 1.5 eq) and LiCl (2.25 g, 53 mmol, 2 eq) was dissolved in a mixture of EtOH (100 ml) and toluene (100 ml). 1M aqueous Na ₂ CO ₃ (66 ml, 66 mmol) was added and the mixture was degassed with argon for 45 min. Pd (PPh ₃ ) ₄ (3.06 g, 2.65 mmol, 0.1 eq) was added and the mixture was stirred overnight at 75-85 ° C. under an argon atmosphere. Volatiles were removed under reduced pressure and the residue was redissolved in EtOAc (500 ml). The solution was washed with water, saturated NaHCO ₃ (100 ml) and brine (100 ml). After drying with a mixture of MgSO ₄ and decolorizing charcoal, the mixture was filtered and concentrated under reduced pressure. The residual oil was triturated with a mixture of TBME (20 ml) and hexane (40 ml), cooled in ice, the precipitated solid was collected by filtration, washed with 25% cold TBME in hexane and dried (3.09 g) . The filtrate and the washings from the above trituration were combined, concentrated and purified by flash chromatography using 10-25% EtOAc in hexanes to give an additional 4.36 g of product. The total yield of 2- (3-furyl) indole of Example 3 was 8.25 g.
Example 4:

Methyl 3-cyclohexyl-1-methyl-6-indolecarboxylate:
Methyl 3-cyclohexyl-6-indolecarboxylate (150.00 g, 0.583 mol) from Example 2 was charged into a 3 L 3-neck flask equipped with a mechanical stirrer and purged with nitrogen gas. DMF (1 L) was added and the solution was cooled in an ice bath. NaH (60% oil dispersion, 30.35 g, 0.759 mol, 1.3 eq) was added in portions (15 minutes) and the mixture was cooled and stirred for 1 hour. Iodomethane (54.5 ml, 0.876 mol, 1.5 eq) was added in portions to maintain the internal temperature at 5-10 ° C. The reaction mixture was then stirred overnight at room temperature. The reaction was stopped by pouring into ice-water (3 L), resulting in the formation of a cream colored precipitate. The material was collected by filtration, washed with water and dried in vacuo at 45 ° C. (137.3 g, 86% yield).
Methyl 2-bromo-3-cyclohexyl-1-methyl-6-indolecarboxylate:
The 1-methylindole derivative (136.40 g, 0.503 mol) from above was charged into a 5 L 3-neck flask equipped with a mechanical stirrer and purged with nitrogen gas. CHCl ₃ (750 ml) and THF (750 ml) were added and the solution was cooled to 0 ° C. Pyridine tribromide (pyridinium bromide perbromide, 185.13 g, 0.579 mol, 1.15 eq) was added in portions and the mixture was stirred at 0 ° C. for 1 hour. The solvent was removed under reduced pressure at room temperature and the residue was dissolved in EtOAc (3 L). The solution was washed with water and brine, dried (decolorizing charcoal / MgSO ₄ ) and concentrated under reduced pressure. The residue was suspended in TBME and heated to 50 ° C. The suspension was stored in the refrigerator overnight and the cream crystalline product was collected by filtration. It was washed with TBME and dried in vacuo (134.3 g, 76% yield).
Example 5:
Cyclohexyl-methyl-tributylstannanyl-1H-indole-6-carboxylic acid methyl ester:

The bromoindole derivative of Example 4 (2.70 g, 7.71 mmol) was dissolved in dry THF (40 ml) and the solution was cooled to −78 ° C. under an argon atmosphere. A solution of nBuLi in hexane (1.4M, 6.90 ml, 9.64 mmol, 1.25 eq) was added dropwise over 15 minutes and stirring at low temperature was continued for 75 minutes. To the resulting suspension was added nBu ₃ SnCl (2.93 ml, 10.8 mmol, 1.4 eq) over 5 minutes. The suspension was dissolved and the solution was stirred at −78 ° C. for 1 hour. The reaction mixture was warmed to room temperature and THF was removed under reduced pressure. The residue was dissolved in TBME (150 ml), washed with 1: 1 brine-water and dried over MgSO ₄ . The material was purified by chromatography on silica gel, which had already been deactivated by mixing with a solution of 5% Et ₃ N in hexane. The same solvent was used as an eluent for chromatography. The title stannane was isolated as a yellow oil (3.42 g, 79% yield).
Example 6:
General Procedure for Stille Cross Coupling of 2-Stannane Indole of Example 5 with Aromatic / Heteroaromatic Halides Aromatic / Heteroaromatic Halides or Pseudohalides (preferably bromides, with the stannane derivatives of Example 5 (Iodide and triflate) cross coupling can be performed using any variation of conventional metal catalyzed still cross couplings as described in the literature. The following examples can be used to illustrate such a method.
3-cyclohexyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carboxylic acid methyl ester:

The stannane derivative of Example 5 (3.42 g, 6.1 mmol) was dissolved in DMF (10 ml) and CuI (0.116 g, 0.61 mmol, 0.1 eq), LiCl (0.517 g, 12.21 mmol, 2 eq), triphenylphosphine ( 0.320 g, 1.22 mmol, 0.2 eq) and 2-bromopyridine (0.757 ml, 7.94 mmol, 1.3 eq) were added. The solution was degassed with a stream of argon (30 minutes) and Pd (PPh ₃ ) ₄ (0.352 g, 0.31 mmol, 0.05 eq) was added. After purging with argon for an additional 10 minutes, the solution was heated and stirred at 100 ° C. overnight under an argon atmosphere. DMF was then removed in vacuo and the residue was dissolved in EtOAc (150 ml). The solution was washed with 1N NaOH (25 ml) and brine (25 ml) and dried over MgSO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with CHCl ₃ then 5-10% EtOAc in CHCl ₃ (1.516 g, 71% yield).
Example 7:
General procedure for the still cross-coupling of 2-bromoindole with aryl or heteroarylstannanes:
3-cyclohexyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carboxylic acid methyl ester:

The 2-bromoindole derivative of Example 4 (0.150 g, 0.428 mmol) and 2-trimethylstannylthiophene (SF Thames et al., J. Organometal. Chem. 1972, 38, 29; 0.150 g, 0.61 mmol, 1.4 eq) Dissolved in dry THF (7 ml) in a sealed tube and the solution was degassed with a stream of argon for 30 min. Pd (Cl) ₂ (PPh ₃ ) ₂ (0.018 g, 0.026 mmol, 0.06 equiv) was added and the tube was sealed. The solution was heated to 80 ° C. for 40 hours. The reaction mixture was cooled to room temperature, EtOAc (10 ml) was added and the suspension was filtered. After evaporation of the solvent, the residue was subjected to the reaction conditions again with additional 2-stannylthiophene (0.150 g, 0.61 mmol) and catalyst (0.020 g) for an additional 20 hours. After cooling to room temperature and filtering the solid, the solvent was evaporated and the residue was purified by flash chromatography using 15-100% CHCl ₃ in hexane as eluent (0.133 g, 88% yield).
The same procedure can be used to couple a stannane derivative to the 2-bromoindole of Example 2.
Example 8:
General procedure for N-alkylation of 2-aryl and 2-heteroaryl-6-indolecarboxylates:
3-cyclohexyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carboxylic acid methyl ester:

NaH (60% oil dispersion, 0.186 g, 4.64 mmol, 1.5 eq) was washed with hexane (20 ml) to remove the oil and then resuspended in DMF (5 ml). After cooling to 0 ° C. in an ice bath, the indole derivative of Example 3 (1.000 g, 3.09 mmol) was added dropwise as a solution in DMF (3 ml + 2 ml rinse). After stirring for 15 minutes, iodomethane (0.385 ml, 6.18 mmol, 2 eq) was added in one portion and the mixture was stirred at low temperature for 2 hours and at room temperature for an additional 2 hours. The reaction was then stopped by the addition of 1N HCl (1 ml) and diluted with TBME (100 ml). The solution was washed with 1N HCl (25 ml) and dried (MgSO ₄ ). After removing volatiles under reduced pressure, the residue was purified by flash chromatography using 5-10% EtOAc in hexane as eluent to give the title compound as a white solid (0.903 g, 86% yield). It was.
Using similar procedures, other N-alkylindole derivatives within the scope of the present invention could be prepared from appropriate electrophiles (eg, EtI, iPrI, iBuI, BnBr).
Example 9:
General procedure for the saponification of 6-indolecarboxylate to the corresponding free carboxylic acid This procedure applies to both indole and N-methylindolecarboxylates.
3-cyclohexyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carboxylic acid:

The 6-indolecarboxylate of Example 6 (1.517 g, 4.35 mmol) was dissolved in DMSO (8 ml) and 5N NaOH (4.4 ml) was added. The mixture was stirred at 50 ° C. for 30 minutes. The solution was then cooled to room temperature and added dropwise to water (15 ml). Insoluble black impurities were removed by filtration and AcOH (2 ml) was added dropwise to the filtrate. The white precipitate that formed was collected by filtration, washed with water and dried (1.37 g, 94% yield).
Example 10:
1-cyclohexyl-2-phenyl-1H-indole-5-carboxylic acid:

Ethyl 4-amino-3-iodobenzoate:
Ethyl 4-aminobenzoate (15.00 g, 91 mmol) and iodine (11.80 g, 46.5 mmol) were mixed with water (80 ml) and chlorobenzene (4.60 g, 41 mmol). The mixture was stirred while the temperature was gradually increased to 90 ° C. over 30 minutes. Hydrogen peroxide (30%, 50 ml) was added at 90 ° C. over 10 hours. After stirring for an additional 6 hours at that temperature, the mixture was cooled and the solution was decanted from the residual solids. The solid was dissolved in DCM and the solution was washed successively with sodium thiosulfate and brine. After drying (MgSO ₄ ), the solvent was removed under reduced pressure and the resulting brown solid was triturated with hexane to remove diiodinated byproducts. The desired compound was obtained as a brown solid (22.85 g, 86% yield).
Ethyl 4-acetamido-3-iodobenzoate:
The previous aniline (1.00 g, 3.44 mmol) was dissolved in pyridine (5 ml) and the solution was cooled in ice. AcCl (0.32 ml, 4.47 mmol, 1.3 eq) was added dropwise and the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 2 hours. The reaction mixture was then diluted with 1N HCl and the product was extracted with TBME (100 ml). The organic phase was washed with 1N HCl (50 ml), dried (MgSO ₄ ) and concentrated to give the desired material as a tan solid (1.121 g, 97% yield).
Ethyl 2-phenyl-indole-5-carboxylate:
According to the procedure of A. Bedeschi et al. (Tet. Lett. 1997, 38, 2307), the previous acetanilide derivative (0.900 g, 2.7 mmol) was converted to PdCl ₂ (5 ml) in a mixture of dioxane (5 ml) and tetramethylguanidine (5 ml). Reacted with phenylacetylene (0.385 ml, 3.5 mmol, 1.3 eq) in the presence of PPh ₃ ) ₂ (10 mol%) and CuI (10 mol%). The desired 2-phenylindole (0.589 g, 82% yield) was isolated as a yellow solid after flash chromatography with 15% EtOAc in hexane.

1-cyclohex-1-enyl-2-phenyl-1H-indole-5-carboxylic acid ethyl ester:
The previous 2-phenylindole derivative (0.265 g, 1.0 mmol) was dissolved in DMF (2 ml) and cesium hydroxide monohydrate (0.208 g, 1.2 mmol, 1.2 eq) was added. The solution was cooled in an ice bath and 3-bromocyclohexene (0.193 g, 1.2 mmol, 1.2 eq) was added dropwise as a solution in DMF (1 ml) (5 min). The mixture was stirred at 0 ° C. for 30 minutes. The reaction was diluted with water (25 ml) and extracted with Et ₂ O ( ₂ × 50 ml) and the extract was dried over MgSO ₄ . The solvent was evaporated under reduced pressure to give a white foam (0.095 g) which was used in the next step without purification.
1-cyclohexyl-2-phenyl-1H-indole-5-carboxylic acid:
The crude indole from above was hydrogenated with 20% Pd (OH) ₂ / carbon in EtOH at room temperature for 20 hours in the usual manner (1 atm H ₂ gas). After filtration of the catalyst, EtOH was removed under reduced pressure.
The residue was dissolved in a mixture of MeOH (1 ml) and DMSO (1 ml) and 5N NaOH (0.5 ml) was added. The mixture was stirred at 50 ° C. overnight. The reaction mixture was cooled and water (10 ml) was added. After acidification with 1N HCl, the product was extracted with Et ₂ O (70 ml) and the solution was dried (Na ₂ SO ₄ ). Evaporate the solvent to obtain a green residue consisting of a 2: 1 mixture (85 mg) of the desired 1-cyclohexyl-2-phenylindole-5-carboxylic acid and 1,3-dicyclohexyl-2-phenylindole-5-carboxylic acid. Obtained.
Example 11:
1-cyclohexyl-3-methyl-2-phenyl-1H-indole-5-carboxylic acid:

Ethyl 2-phenyl-3-methyl-indole-5-carboxylate:
Adapting the procedure of HC Zhang (Tet. Lett. 1997, 38, 2439), ethyl 4-amino-3-iodobenzoate (from Example 10, 0.500 g, 1.72 mmol) was dissolved in DMF (5 ml), LiCl (0.073 g, 1.72 mmol, 1 eq), PPh ₃ (0.090 g, 0.34 mmol, 0.2 eq), K ₂ CO ₃ (1.188 g, 8.6 mmol, 5 eq) and phenylpropyne (0.645 ml, 5.76 mmol, 3 eq) Equivalent) was added. The solution was degassed by purging with argon for 1 h and palladium acetate (0.039 g, 0.17 mmol, 0.1 equiv) was added. The mixture was stirred at 80 ° C. for 20 hours under an argon atmosphere. The reaction mixture was diluted with water (25 ml) and extracted with EtOAc (50 ml). The extract was washed with brine (3 × 25 ml) and dried (MgSO ₄ ). Concentrate in vacuo and purify by flash chromatography using 10-15% EtOAc-hexanes to obtain the desired 2-phenyl-3-methylindole (0.275 g, least polar component) and 3-phenyl-2- The methyl isomer (0.109 g, more polar component) was obtained.

Ethyl 1- (3-cyclohexenyl) -3-methyl-2-phenylindole-5-carboxylate:
The earlier less polar isomer (0.264 g, 0.95 mmol) was dissolved in DMSO (2 ml) and cesium hydroxide monohydrate (0.191 g, 1.14 mmol, 1.2 eq) followed by 3-bromocyclohexene (0.183). g, 1.14 mmol, 1.2 eq in 0.7 ml DMSO) was added. The mixture was stirred at room temperature for 30 minutes. Additional CsOH monohydrate (0.400 g, 2.4 eq) and 3-bromocyclohexene (0.400 g, 2.4 eq) were added and stirring was continued for another 30 minutes. Similar amounts of the two reagents were added again and after another 30 minutes of stirring at room temperature, the reaction was diluted with 1N HCl (6 ml) and water (20 ml). The product was extracted with TBME (100 ml), dried (MgSO ₄ ) and after concentration under reduced pressure, the residue was purified by flash chromatography using 5-10% EtOAc in hexane as eluent. The desired N-alkylated indole was obtained (0.130 g).
Ethyl 1-cyclohexyl-3-methyl-2-phenylindole-5-carboxylate:
The previous unsaturated product was hydrogenated with 20% Pd (OH) ₂ in EtOH for 3 hours at room temperature in the usual manner (1 atm H ₂ gas).
1-cyclohexyl-3-methyl-2-phenyl-1H-indole-5-carboxylic acid:
The previous hydrogenated material was dissolved in a mixture of DMSO (2 ml) and MeOH (2 ml). 5N NaOH (0.5 ml) was added and the mixture was stirred at 60 ° C. overnight. After dilution with water (40 ml), the product aqueous phase was washed with a 1: 1 mixture of Et ₂ O-hexane (50 ml) and then acidified to pH 1 with 1N HCl. The released free acid was extracted with diethyl ether (2 × 50 ml) and the extract was dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give the desired indole as a light brown solid (0.074 g).
Example 12:
2-Bromo-3-cyclopentyl-1-methyl-1H-indole-6-carboxylic acid methyl ester:

Indole 6-carboxylic acid (220 g, 1.365 mol) and KOH pellets (764.45 g, 13.65 mol, 10 equivalents) were charged into a 3 L three-necked flask equipped with a mechanical stirrer. Water (660 ml) and MeOH (660 ml) were added and the mixture was heated to 75 ° C. Using a pump, cyclopentanone (603.7 ml, 6.825 mol, 5 eq) was added dropwise over 18 hours. The reaction mixture was heated for an additional 3 hours (after which the reaction was judged complete by HPLC) and cooled to 0 ° C. over 1 hour. The precipitated potassium salt was collected by filtration and washed with TBME (2 × 500 ml) to remove the cyclopentanone self-condensation product. The brown solid was redissolved in water (2.5 L) and the solution was washed with TBME (2 × 1 L). After acidifying to pH 3 with concentrated HCl (425 ml), the beige precipitate was collected by filtration, washed with water (2 × 1 L) and dried in vacuo at 70 ° C. The crude product weighed 275.9 g (88.9% mass recovery) and had 85% homogeneity (HPLC).
The crude product from above (159.56 g, 0.70 mol) was dissolved in MeOH (750 ml) and 20% Pd (OH) ₂ / charcoal (8.00 g) was added. The mixture was hydrogenated in a Parr apparatus under hydrogen gas at 3.5 kg / cm ² (50 psi) for 18 hours. After completion, the catalyst was removed by filtration through celite and the solvent was removed under reduced pressure. The resulting brown solid was dried in vacuo at 70 ° C. for 12 hours. The crude product (153.2 g) was obtained as a brown solid, which was 77% homogeneous by HPLC.
The crude 3-cyclopentylindole-6-carboxylic acid (74.00 g, 0.323 mol) was charged into a 3 L 3-neck flask equipped with a mechanical stirrer and thermometer. The system was purged with nitrogen gas and anhydrous DMF (740 ml) was added. After dissolution of the starting material, anhydrous potassium carbonate (66.91 g, 0.484 mol, 1.5 eq) was added and the mixture was stirred for 5 minutes. Iodomethane (50 ml, 0.807 mol, 2.5 eq) was added and the mixture was stirred for 5 hours, after which HPLC analysis of the reaction mixture showed 97% conversion to its methyl ester.

The reaction mixture was cooled in an ice bath and sodium hydride (95%, oil free, 10.10 g, 0.420 mol, 1.3 eq) was added in portions over 3 minutes (exotherm: 8 ° C. to 30 ° C. internal). Temperature rise). After stirring for an additional 15 minutes, the cooling bath was removed and stirring continued at room temperature for 1.5 hours, after which no further progress was observed (HPLC). Additional NaH (1.55 g, 65 mmol, 0.2 eq) and iodomethane (1.0 ml, 16 mmol, 0.05 eq) were added and stirred for 15 min before the reaction was judged complete by HPLC (96% N -Methylation).
The reaction mixture was slowly poured into water (4 L) with vigorous stirring (2 minutes) and after 10 minutes acidified with concentrated HCl (85 ml) to pH <2. The mixture was stirred for 5 minutes to allow complete conversion of residual potassium carbonate and potassium bicarbonate to more soluble chloride. The pH was adjusted to about 7 with 4N NaOH (40 ml) and the mixture was stirred overnight at room temperature. The precipitated material was collected by filtration, washed with water (600 ml) and dried at 60 ° C. in vacuo. The crude product (79% homogeneity by HPLC) was obtained as a brown solid (72.9 g).
The crude material from above was triturated with a minimum amount of MeOH to remove a series of trace impurities. The solid was then collected by filtration and dissolved in a minimal amount of hot EtOAc. After cooling to room temperature, hexane was added (5 volumes) and the mixture was cooled in ice and filtered. The filtrate was then evaporated and dried to give the desired product.
The previous N-methylindole (10.60 g, 41.2 mmol) was dissolved in isopropyl acetate (150 ml) and sodium acetate (5.07 g, 62 mmol, 1.5 eq) was added. The suspension was cooled in an ice bath and bromine (2.217 ml, 43.3 mmol, 1.05 equiv) was added dropwise over 2 minutes. The pale tan suspension turned dark red (exotherm from 5 ° C to 13 ° C). It was stirred at 0 ° C. for 1 hour. The reaction was completed as shown by HPLC analysis by adding additional bromine (0.21 ml, 4.2 mmol, 0.10 equiv). The reaction was then stopped by the addition of 10% aqueous sodium sulfite (15 ml) followed by water (50 ml) and K ₂ CO ₃ (10.6 g, 1.8 eq) to neutralize HBr. The organic layer was separated, washed with 10% aqueous sodium sulfite and aqueous K ₂ CO ₃ and dried (MgSO ₄ ). The solvent was removed under reduced pressure and the residue co-evaporated with TBME (75 ml) to give a beige solid that was dried in vacuo overnight (13.80 g). The crude material was triturated with boiling MeOH (80 ml) for 30 minutes, cooled in ice and a beige solid was collected by filtration. The product was dried in vacuo at 60 ° C. (10.53 g, 76% recovery).
Example 13
3-Cyclopentyl-1-methyl-2-vinyl-1H-indole-6-carboxylic acid:

To the 2-bromoindole derivative of Example 12 (2.044 g, 6.08 mmol) in dry dioxane (20 ml) was added vinyltributyltin (1.954 ml, 6.69 mmol). The solution was degassed by bubbling nitrogen for 15 minutes. Bis (triphenylphosphine) palladium (II) chloride (213.4 mg, 0.304 mmol) was then added and the reaction mixture was heated at 100 ° C. overnight. The reaction mixture was diluted with ether and washed successively with water and brine. After normal treatment (MgSO ₄ , filtration and concentration), the residue was subjected to flash chromatography (5 cm, 10% AcOEt-hexane) to give the desired compound (1.32 g, 4.70 mmol, 77% yield) as a white solid. It was. To the previous ester (153 mg, 0.54 mmol) in a mixture of THF (2.8 ml) and methanol (1.4 ml) was added an aqueous solution of lithium hydroxide (226.6 mg in 1.6 ml of water, 5.40 mmol). The reaction mixture was stirred at 50 ° C. for 1.5 hours and diluted with water. The aqueous layer was acidified with 1M aqueous HCl and extracted three times with CH ₂ Cl ₂ . The combined organic layers were washed successively with water (2X) and brine. After usual treatment (MgSO ₄ , filtration and concentration), the desired crude acid was isolated (150 mg).
Example 14
3-Cyclohexyl-1-methyl-2-oxazol-5-yl-1H-indole-6-carboxylic acid:

To the bromide of Example 4 (1.00 g, 2.855 mmol) in dry dioxane (10 ml) was added vinyltributyltin (917.8 μL, 3.141 mmol). The solution was degassed by bubbling nitrogen over 15 minutes. Bis (triphenylphosphine) palladium (II) chloride (101 mg, 0.144 mmol) was then added and the solution was refluxed for 7 hours. The reaction mixture was diluted with ether and washed successively with water and brine. Normal processing (MgSO _4, filtered and concentrated) after the residue purified by flash chromatography (5 cm, hexane to 2.5% of AcOEt～10% of AcOEt～5% AcOEt-hexane) toward the desired compound (773 mg, 2.60 mmol, Yield 91%) was obtained as a pale yellow solid.
The previous olefin derivative (100 mg, 0.336 mmol) in a mixture of acetone (690 μL), tert-butanol (690 μL) and water (690 μL) was added to N-methylmorpholine N-oxide (NMMO; 48 mg, 0.410 mmol) and tert -A 2.5% solution (33 μL) of osmium tetroxide in butanol was added continuously. The reaction mixture was stirred for 3 days at room temperature and then concentrated. The residue was dissolved in EtOAc and washed successively with water (2X) and brine. After normal treatment (MgSO ₄ , filtration and concentration), the crude diol (117 mg) was isolated.
To the crude diol obtained previously (about 0.336 mmol) in a mixture of THF (3.2 ml) and water (3.2 ml) at 0 ° C., sodium periodate (86.2 mg, 0.403 mmol) was added. The cooling bath was then removed and the reaction mixture was stirred at room temperature for 1 hour 45 minutes, then AcOEt was added. The resulting solution was washed successively with 10% aqueous citric acid solution, water, saturated aqueous NaHCO ₃ solution, water (2 ×) and brine. After the usual treatment (MgSO ₄ , filtration and concentration), the desired crude aldehyde was isolated (92 mg, 0.307 mmol, 91% yield).
A mixture of the previous aldehyde (25.8 mg, 0.086 mmol), anhydrous potassium carbonate (12.4 mg, 0.090 mmol) and Tosmic (17.57 mg, 0.090 mmol) in anhydrous MeOH (500 μL) was refluxed for 2 hours. AcOEt was then added and the mixture was washed successively with water (2X) and brine. After normal treatment (MgSO ₄ , filtration and concentration), the desired crude oxazole was isolated (28 mg, 0.083 mmol, 96% yield).
To the previous ester (28 mg, 0.083 mmol) in a mixture of THF (425 μL), MeOH (210 μL) and water (250 μL) was added lithium hydroxide (34.8 mg, 0.830 mmol). The reaction mixture was stirred at room temperature overnight, then diluted with water and acidified with 1N aqueous HCl. The aqueous layer was extracted with dichloromethane (3X) and washed successively with water (2X) and brine. After normal treatment (MgSO ₄ , filtration and concentration), the title crude acid was isolated (30 mg).
Example 15
2- (1H-Benzimidazol-2-yl) -3-cyclohexyl-1-methyl-1H-indole-6-carboxylic acid:

To a mixture of the aldehyde from Example 14 (28 mg, 0.094 mmol) and 1,2-diaminobenzene (10.9 mg, 0.101 mmol) in acetonitrile (500 μL) and DMF (200 μL) is added chloranil (24.8 mg, 0.101 mmol). Added. The reaction mixture was stirred at room temperature for 3 days. AcOEt was added and the reaction mixture was washed successively with 1N aqueous NaOH (2X), water (4X) and brine. After normal treatment (MgSO ₄ , filtration and concentration), the residue was subjected to flash chromatography (1 cm, 30% AcOEt-hexane) to give the desired benzimidazole ester derivative (11 mg, 0.028 mmol, 30% yield).
To the previous ester (11 mg, 0.028 mmol) in a mixture of THF (240 μL), MeOH (120 μL) and water (140 μL) was added lithium hydroxide (11.7 mg, 0.280 mmol). The reaction mixture was stirred at room temperature overnight, then diluted with water and acidified with 1N aqueous HCl. The aqueous layer was extracted with dichloromethane (3X) and washed successively with water (2X) and brine. After normal treatment (MgSO ₄ , filtration and concentration), the title crude acid was isolated (9 mg, 0.0241 mmol, 86% yield).
Example 16
3-Cyclopentyl-1-methyl-1H-indole-2,6-dicarboxylic acid 6-methyl ester:

3-cyclopentylaldehyde (20 mg, 0.07 mmol) and 2-methyl-2-butene (541 μL, 5.11 mmol) prepared in a manner similar to that described in Example 15 in tert-butanol (500 μL) at 0 ° C. ) Was added a freshly prepared solution of sodium chlorite (64.2 mg, 0.711 mmol) in phosphate buffer (98 mg NaH ₂ PO _{4 in} 150 μL water). The reaction mixture was stirred at room temperature for 45 minutes and then brine was added. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed successively with 0.5N aqueous HCl and brine. After normal treatment (MgSO ₄ , filtration and concentration), 23.1 mg of the desired crude acid was isolated as a yellow solid.
Example 17
2-Bromo-3-cyclopentyl-benzofuran-6-carbonitrile:

To a solution of 3-bromophenol (10 g, 57.8 mmol) in 1,2-dichloroethane (50 ml), AlCl ₃ (11.5 g, 86.2 mmol) was carefully added in two equal portions at room temperature. Cyclopentanecarbonyl chloride (7.7 g, 58.1 mmol) was then added dropwise via syringe at room temperature. The reaction solution was then heated to reflux under a N ₂ atmosphere for a period of 2 hours. The reaction solution was cooled to room temperature and carefully poured into 100 ml of 1N HCl ice slush. After stirring gently for several minutes, the phases were separated and the aqueous phase was extracted with 1,2-dichloroethane. The organic phases were combined, washed with water and brine and dried over MgSO ₄ . The solvent was removed under reduced pressure and the residue was purified on a pad of silica gel with hexane. 17.2 g (78%) of product was collected as a yellow liquid / low melting solid. To a solution of the previous phenol (12.2 g, 45.3 mmol) in 80 ml DMF at 0 ° C. was added 60% NaH (2.67 g, 66.7 mmol). The ice bath was removed and the reaction solution was stirred for 30 minutes. Ethyl bromoacetate (11.4 g, 68.3 mmol) was then added dropwise via a syringe. A mild exotherm (about 40 ° C.) was observed and the reaction solution was stirred at room temperature for 1 hour. The reaction mixture was carefully poured into 150 ml ice water and then acidified to pH 4-5 with 1N HCl. The reaction mixture was then extracted with EtOAc. The phases were separated and the organic fraction was washed with saturated NaHCO ₃ , water and brine, then dried over MgSO ₄ . The solvent was removed under reduced pressure. The crude material was used as such for the next step and processed as a theoretical yield.
16.1 g (45.3 mmol) of the previous crude ester was combined with 61 ml of 1N NaOH and 137 ml of THF and stirred overnight at room temperature (additional 1N NaOH may be added if starting material is present). After hydrolysis, THF was stripped off and the aqueous phase was extracted with EtOAc, which was discarded. The aqueous phase was then acidified to pH 2-3 with 1N HCl and extracted with EtOAc. The phases were separated and the organic phase was washed with water and brine then dried over MgSO ₄ . The solvent was removed under reduced pressure. The crude material was used as such for the next step and processed as a theoretical yield.
13.3 g (40.7 mmol) of the crude acid from above was dissolved in 200 ml of Ac ₂ O. NaOAc (6.7 g, 81.7 mmol) was added and the resulting mixture was refluxed for 5 hours under N ₂ atmosphere. The heat was removed and the reaction mixture was cooled to room temperature. The reaction solution was then diluted with 100 ml of toluene and neutralized with ice / 6N NaOH (strong exotherm). The phases were separated and the aqueous phase was extracted with EtOAc. The organic fractions were combined and washed with water and brine, then dried over MgSO ₄ . The solvent was removed under reduced pressure and the residue was purified on a pad of silica gel with petroleum ether. 7.8 g (72%) of product was collected as a clear liquid / low melting solid.

The previous bromobenzofuran (29.6 g, 111.6 mmol) was dissolved in 60 ml DMF. CuCN (12.0 g, 134.0 mmol) was added and the resulting mixture was refluxed for 7 hours under N ₂ atmosphere. The heat was removed and the reaction mixture was cooled to room temperature. The reaction solution was poured into 300 ml of 5% aqueous NaCN and 200 ml of EtOAc was added. The resulting solution was gently stirred until all solids were dissolved in the solution. The layers were separated and the aqueous fraction was extracted with EtOAc. The organic fractions were combined and washed with 5% aqueous NaCN, water and brine, then dried over MgSO ₄ . The solvent was removed under reduced pressure. The brown crude solid was purified on a pad of silica gel with 10% EtOAc / hexane and then purified by recrystallization in hexane.
A solution of N-bromosuccinimide (5.340 g, 30 mmol) in DMF (20 ml) was added dropwise to a solution of the previous benzofuran derivative (2.00 g, 9.47 mmol) in DMF (20 ml). The mixture was stirred at room temperature overnight, after which bromination was judged complete (HPLC). The reaction mixture was diluted with EtOAc and washed successively with water (3X) and brine. After drying (MgSO ₄ ), the solvent was removed under reduced pressure and the residue was purified by flash chromatography using 3% EtOAc in hexanes to give the title 2-bromobenzofuran derivative as a white solid (1.45 g, 53% yield). %).
Example 18
3-Cyclopentyl-2-pyridin-2-yl-benzofuran-6-carboxylic acid:

2-Bromobenzofuran derivative of Example 17 (0.850 g, 2.93 mmol), 2-tri (n-butyl) stannylpyridine (1.362 g, 3.7 mmol), triphenylphosphine (0.760 g, 2.90 mmol), lithium chloride ( 0.250 g, 5.9 mmol) and CuI (0.057 g, 0.3 mmol) were dissolved in DMF (30 ml) and the mixture was degassed by bubbling argon over 30 min. Tetrakis (triphenylphosphine) palladium (0.208 g, 0.18 mmol) was added and the mixture was stirred at 100 ° C. under an argon atmosphere. After 19 hours, the reaction was cooled to room temperature, poured into water (70 ml) and extracted with TBME. The organic phase was washed with water (2X) and brine, dried (MgSO ₄ ) and concentrated to give a residue that was purified by flash chromatography. The desired 2 (2-pyridyl) benzofuran derivative (0.536 g, 63% yield) was obtained as a white solid. The previous nitrile (0.200 g, 0.694 mmol) was suspended in a mixture of concentrated H ₂ SO ₄ (5 ml), AcOH (4 ml) and water (2 ml). After refluxing for 1.5 hours, TLC showed complete hydrolysis. The mixture was cooled in ice and 10N NaOH was added dropwise to pH 9. The aqueous layer was washed with dichloromethane and then acidified to pH 6 with 5N HCl. The product was extracted with EtOAc, dried (MgSO ₄ ) and the solvent removed in vacuo. The desired carboxylic acid was obtained as a white solid.
Example 19
2-Bromo-3-cyclopentyl-benzo [b] thiophene-6-carboxylic acid ethyl ester

To a solution of Example 17 3-bromo-6-cyclopentanecarbonylphenol (5.194 g, 19.30 mmol) in DMF (58.0 ml), 1,4-diazabicyclo [2.2.2] octane (4.33 g, 38.60 mmol) And dimethylthiocarbamyl chloride (4.77 g, 38.6 mmol) was added at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was acidified to pH 3 with 1N HCl and extracted with EtOAc. The organic layers were combined, washed with brine and dried over MgSO ₄ . The crude mixture was purified with a plug of silica gel using 3% EtOAc / hexanes to give 6.976 g (100%) of the desired thiocarbamate as a colorless oil.
The neat O-3-bromo-6-cyclopentanecarbonyl N, N-dimethylthiocarbamate (43.147 g, 121.1 mmol) from above was heated to an internal temperature of 180-190 ° C. for 5 hours. The reaction progress was monitored using TLC (20% EtOAc / hexanes; R _f 0.6 (starting material), 0.5 (product)). The crude material was used in the next reaction without further purification.
The crude S-3-bromo-6-cyclopentanecarbonyl N, N-dimethylthiocarbamate from above is dissolved in MeOH (600 ml), KOH (40.0 g, 714 mmol) is added and the mixture is heated for 1.5 hours. , Refluxed. The mixture was cooled to room temperature and the solvent was removed by rotary evaporation. The residue was dissolved in water and acidified to pH 3 with 6N HCl. It was extracted with EtOAc and the crude product was purified by silica gel chromatography using 1-5% EtOAc / hexane. 31.3 g (91%) of the desired thiophenol derivative was obtained as a yellow oil.

To a solution of the previous 3-bromo-6-cyclopentanecarbonylthiophenol (0.314 g, 1.105 mmol) in acetone (5.0 ml) was added K ₂ CO ₃ (0.477 g, 3.45 mmol) followed by ethyl. Bromoacetate (0.221 g, 0.147 ml, 1.33 mmol) was added. The mixture was stirred overnight. The reaction mixture was filtered through filter paper and the filtrate was concentrated. Purification on silica gel using 5% EtOAc / hexanes afforded 0.334 g (82%) of product as a colorless oil.
The crude ester from above was dissolved in THF (12.0 ml) and 1N NaOH (5.0 ml) was added at room temperature. The mixture was stirred at room temperature for 2-3 hours or until TLC showed a complete reaction. The solvent was removed by rotary evaporation. Water was added and the mixture was acidified to pH 3 with 6N HCl, extracted with EtOAc, washed with brine and dried over MgSO ₄ . The solvent was removed under reduced pressure and the residue was used without further purification.
To the crude acid from above, acetic anhydride (16.0 ml) was added followed by NaOAc (0.573 g) and the mixture was heated to reflux overnight. The mixture was cooled to room temperature and poured into a mixture of ice and toluene. 6N NaOH was added to a pH of about 7, extracted with EtOAc, washed with brine and dried over MgSO ₄ . The solvent was removed by rotary evaporation and the residue was purified on silica gel with hexanes to give 0.795 g (80%) of 6-bromo-3-cyclopentylbenzothiophene as a colorless oil.
A mixture of the above 6-bromo-3-cyclopentylbenzothiophene (0.723 g, 2.57 mmol) and copper cyanide (0.272 g, 3.04 mmol) in DMF (1.4 ml) was heated to reflux overnight. The mixture was cooled to room temperature and diluted with EtOAc. 2N NH ₄ OH was added and the mixture was stirred for 10 min and filtered through celite. The aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over MgSO ₄ and the solvent removed under reduced pressure. The product was used without further purification.
3-Cyclopentyl-6-cyanobenzothiophene (17.65 g, 77.65 mmol) was dissolved in acetic acid (310 ml) and bromine (49.64 g, 310.6 mmol) was added at room temperature. The mixture was stirred overnight at room temperature and the reaction progress was monitored using HPLC. After the reaction was complete, toluene was added to the reaction mixture to remove acetic acid (3 × 100 ml). The crude product was dried under reduced pressure and used without further purification.
The crude cyano derivative from above was added to ethanol (150 ml, denatured) and concentrated H ₂ SO ₄ (45 ml) and the mixture was heated to reflux for 1-2 days. After completion (HPLC), the reaction mixture was cooled to room temperature, poured into ice-water, extracted with dichloromethane (5 × 100 ml), the organic layers were combined and washed with 5% NaHCO ₃ and brine. The solvent was removed under reduced pressure and the residue was purified on silica gel with 1% EtOAc / hexane. The collected fractions were concentrated and the residue was slurried in methanol. The solid was filtered and washed with ice cold methanol to give 15.9 g of pure ethyl ester (58%, 2 steps) as a slightly yellow solid.
Example 20
3-Cyclopentyl-2-pyridin-2-yl-benzo [b] thiophene-6-carboxylic acid:

2-bromobenzothiophene (0.354 g, 1.00 mmol) of Example 19, 2-tin (n-butyl) stannylpyridine (0.442 g, 1.2 mmol), triphenylphosphine (0.262 g, 1.00 mmol), lithium chloride ( 0.085 g, 2.0 mmol) and CuI (0.019 g, 0.1 mmol) were dissolved in DMF (10 ml) and the mixture was degassed by bubbling argon for 30 min. Tetrakis (triphenylphosphine) palladium (0.069 g, 0.06 mmol) was added and the mixture was stirred at 100 ° C. under an argon atmosphere. After 24 hours, the reaction was cooled to room temperature, poured into water (70 ml) and extracted with TBME. The organic phase was washed with water (2X) and brine, dried (MgSO ₄ ) and concentrated to give a residue that was purified by flash chromatography. The desired 2 (2-pyridyl) benzothiophene ester (0.197 g, 56% yield) was obtained as a pale yellow waxy solid.
Using NaOH, the previous ester was hydrolyzed in the usual manner to give the title acid, which could be used directly or purified by HPLC and flash chromatography. The acid could be coupled to the amine derivative according to the general procedure described in Example 37.
Example 21
3-Cyclopentyl-2-furan-3-yl-benzo [b] thiophene-6-carboxylic acid:

The 2-bromobenzothiophene ester of Example 19 was coupled to the 3-furanboronic acid described in Example 3 to give the desired 2 (3-furyl) benzothiophene ester in 85% yield. Saponification of the ethyl ester was performed with NaOH at room temperature to give the title carboxylic acid derivative.
Example 22
3-cyclohexyl-1-methyl-2-phenyl-1H-pyrrolo [2,3, b] pyridine-6-carboxylic acid:

7-azaindole (15.00 g, 0.127 mol) was dissolved in MeOH (330 ml) and sodium methoxide (25% w / w in MeOH, 172 ml, 0.753 mol) and cyclohexanone (52.86 ml, 0.51 mol) were added. The mixture was refluxed for 60 hours and then concentrated under reduced pressure. After cooling in ice-water, the reaction mixture was acidified with 3N HCl to pH 8 and the precipitated solid was collected by filtration. The product was washed with water, triturated with TBME-hexane and dried by azeotroping with toluene (19.8 g).
The previous material (15.00 g, 75.65 mmol) was dissolved in a mixture of EtOH (130 ml) and THF (30 ml) and 20% Pd (OH) ₂ / carbon (13.0 g) was added. The mixture was hydrogenated under 1 atm of H ₂ gas over 24 hours, at which point additional catalyst (1.30 g) was added. After stirring for an additional 16 hours under H ₂ gas, the catalyst was removed by filtration and the solution was evaporated under reduced pressure to give a residue that was triturated with TBME to give a tan solid (13.9 g). Obtained.
The previous azaindole derivative (7.50 g, 37.45 mmol) was dissolved in DME (130 ml) and meta-chloroperbenzoic acid (12.943 g, 60.0 mmol) was added. After stirring for 2 hours, the volatiles were removed under reduced pressure and the residue was suspended in water (100 ml). The mixture was basified to pH 10 by addition of saturated aqueous Na ₂ CO ₃ with vigorous stirring. The solid was then collected by filtration, washed with water and a small amount of TBME and dried (7.90 g).
The crude N-oxide from above (4.00 g, 18.49 mmol) was dissolved in DMF (350 ml) and NaH (60% dispersion, 1.52 g, 38 mmol) was added in portions over 5 minutes. The mixture was stirred for 30 minutes and iodomethane (1.183 ml, 19 mmol) was added dropwise to the suspension over 20 minutes. After stirring for 3 hours at room temperature, no further progress was measured by HPLC analysis. The reaction mixture was poured into water and extracted 3 times with EtOAc. The extract was washed with brine, dried (MgSO ₄ ) and evaporated to give a tan solid (3.65 g, 60% homogeneity by NMR), which was used immediately without purification.

The crude product from above (0.80 g, 3.47 mmol) was dissolved in MeCN (10 ml). Triethylamine (1.13 ml, 8.1 mmol) was added followed by trimethylsilylcyanide (2.13 ml, 16 mmol). The solution was then refluxed for 19 hours. After cooling to room temperature, the reaction was quenched by slow addition of aqueous NaHCO ₃ and the product was extracted with EtOAc. The extract was washed with brine, dried (MgSO ₄ ) and concentrated to give a residue that was purified by flash chromatography on silica gel using 15% EtOAc-hexane (0.285 g).
The nitrile (0.300 g, 1.254 mmol) was suspended in EtOH (15 ml) and hydrogen chloride gas was bubbled in over 15 minutes to give a clear solution. The solution was then refluxed for 1.5 hours until TLC showed complete conversion of the starting material. After cooling to room temperature, the volatiles were removed under reduced pressure and the residue was dissolved in EtOAc. The solution was washed with brine, dried (MgSO ₄ ) and concentrated. The residue was purified by flash chromatography on silica gel (15-20% EtOAc-hexane) to give the desired ethyl ester as a pale yellow gum (0.227 g).
The previous ester (0.100 g, 0.35 mmol) was dissolved in THF (4 ml) and pyridinium hydrobromide perbromide (0.200 g, 0.532 mmol) was added. The mixture was stirred in a sealed vial at 65 ° C. for 16 hours (> 80% conversion). The solution was evaporated and the residue was taken up in EtOAc. The solution was washed with water and brine, dried (MgSO ₄ ) and concentrated. The crude material was purified by flash chromatography on silica gel (15% EtOAc-hexane).

Earlier bromide (0.100 g, 0.274 mmol), phenylboronic acid (0.049 g, 0.4 mmol) and lithium chloride (0.019 g, 0.45 mmol) in toluene (2 ml), EtOH (2 ml) and 1M Na ₂ CO ₃ ( 0.43 ml). The mixture was degassed by passing argon gas through the solution for 30 minutes and tetrakistriphenylphosphine palladium (0.035 g, 0.03 mmol) was added. The mixture was refluxed for 18 hours after which time additional catalyst (0.035 g, 0.03 mmol) was added. After refluxing for a further 2 hours, EtOH was removed under reduced pressure. The residue was dissolved in EtOAc and the solution was washed with 10% aqueous HCl and brine and dried (MgSO ₄ ). Volatiles were removed under reduced pressure to give an orange gum which was purified by flash chromatography on silica gel using 20% EtOAc-hexane (0.105 g, crude material).
The previous partially purified ester (0.100 g, 0.276 mmol) was dissolved in a mixture of THF (2 ml) and EtOH (2 ml). 1N NaOH (2.8 ml) was added and the mixture was stirred at room temperature for 4 hours. Volatiles were removed under reduced pressure and the residue was diluted with 10% aqueous HCl. The product was extracted with EtOAc (3X), dried (MgSO _4), and evaporated to give the title compound was purified by reverse phase preparative HPLC.
Example 23
General procedure for the preparation of aromatic amide derivatives from α-monosubstituted N-Boc-amino acids:

N-Boc protected α-monosubstituted amino acids were coupled to aromatic amine derivatives using conventional amide bond coupling reagents. The N-Boc protecting group was then cleaved under acidic conditions and the appropriate amine derivative was isolated as the hydrochloride salt. The following procedure for coupling N-Boc-D-alanine to ethyl 4-aminocinnamate is typical.
(R) -1- [4-((E) -2-Ethoxycarbonyl-vinyl) -phenylcarbamoyl] -ethyl-ammonium chloride:

N-Boc-D-alanine (0.284 g, 1.5 mmol) was dissolved in DMSO (2 ml) and DIEA (1.04 ml, 6 mmol, 4 eq) was added. Ethyl 4-aminocinnamate (0.287 g, 1.5 mmol) was added followed by TBTU (0.578 g, 1.80 mmol) and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with EtOAc (75 ml) and the solution was washed with water (40 ml), 1N NaOH (3 × 25 ml), 1M KHSO ₄ (2 × 25 ml) and 5% NaHCO ₃ (25 ml). The extract was dried (MgSO ₄ ) and concentrated to give the desired N-Boc-protected anilide as a yellow solid (0.411 g). The previous material was stirred with 4N HCl in dioxane (10 ml) for 1 hour. Volatiles were removed under reduced pressure and the residue was triturated with TBME to give the title hydrochloride salt as a brown solid.
Example 24
4- (4-Amino-phenyl) -thiazole-2-carboxylic acid ethyl ester:

4′-nitro-2-bromoacetophenone (6.100 g, 25 mmol) and ethyl thiooxamate (3.460 g, 26 mmol) were dissolved in MeOH (20 ml) and the solution was refluxed for 1 hour. After cooling to room temperature, the precipitated solid was collected by filtration, washed with cold MeOH and dried in vacuo (5.15 g, 75% yield). A suspension of the above nitroester (2.50 g, 8.98 mmol) and 20% Pd (OH) ₂ / carbon (200 mg) in 2: 1 EtOH-THF (60 ml) in 1 atmosphere of hydrogen gas. And stirred for 3 hours. The suspension was filtered to remove the catalyst and the volatiles were removed under reduced pressure to give the title compound as a reddish foam (2.05 g, 92% yield).
Example 25
4- (4-Ethoxycarbonyl-thiazol-2-yl) -phenyl-ammonium chloride:

p-Bromoaniline (13.0 g, 76 mmol) and Boc ₂ O (19.8 g, 91 mmol) were dissolved in toluene (380 ml) and stirred at 70 ° C. for 15 hours. The reaction mixture was cooled to room temperature, evaporated to dryness, redissolved in EtOAc and washed with 0.1 M HCl and brine. The organic solution was dried over anhydrous MgSO ₄ , evaporated to dryness and purified by flash column chromatography using 5% to 10% EtOAc in hexane as eluent to give Boc-protected aniline (23 g). It was. The Boc-protected bromoaniline (10.7 g, 39.2 mmol) was dissolved in anhydrous THF (75 ml) in a flask equipped with an overhead stirrer. The solution was cooled to 0 ° C. and MeLi (1.2 M in Et ₂ O, 33 ml, 39.2 mmol) was added dropwise while maintaining the internal temperature below 7 ° C. The reaction mixture was stirred at 0 ° C. for 15 minutes and then cooled to −78 ° C., after which N-BuLi (2.4 M in hexane, 17 ml, 39.2 mmol) was added dropwise and the internal temperature was below −70 ° C. Maintained. The reaction mixture was stirred at −78 ° C. for 1 h, B (OEt) ₃ (17 ml, 98 mmol) was added dropwise (internal temperature <−65 ° C.), stirring was continued at −78 ° C. for 45 min and 0 ° C. And continued for 1 hour. The reaction mixture was then treated with 5% aqueous HCl (about 100 ml, to pH about 1) for 15 minutes and NaCl (s) was added to saturate the aqueous layer. The aqueous layer was extracted with 0.5 M NaOH (4 × 100 ml) and the combined aqueous layers were acidified with 5% HCl (150 ml, pH˜1) and extracted with Et ₂ O (3 × 200 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated to give N-Boc carbamate of 4-aminophenylboronic acid as a solid (7.5 g).
Thiourea (7.60 g, 100 mmol) and ethyl bromopyruvate (12.6 ml, 100 mmol) were mixed and heated to 100 ° C. for 45 minutes. After cooling the reaction mixture, the resulting solid was triturated with acetone, filtered and recrystallized with EtOH to give the desired aminothiazole product (10.6 g, 40 mmol). The aminothiazole was then added slowly (over a period of 20 minutes) to a solution of t-butylnitrile (6.2 g, 60 mmol) and CuBr ₂ (10.7 g, 48 mmol) in MeCN (160 ml) at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. The mixture was then added to aqueous HCl (20%) and extracted with Et ₂ O ( ₂ × 400 ml). The organic layer was washed with aqueous HCl (10%), dried over anhydrous MgSO ₄ and evaporated to dryness. The desired bromothiazole product was isolated in approximately 85% yield (4.3 g) after flash column chromatography using 15% EtOAc in hexane as the eluent.
To a degassed solution of the bromothiazole product (230 mg, 0.97 mmol) was added a boronic acid derivative (230 mg, 0.97 mmol) and an aqueous Na ₂ CO ₃ solution (2M, 3 ml) in DME (3 ml), a catalytic amount of Pd (PPh ₃ ) ₄ (56 mg, 0.049 mmol) was added and the reaction mixture was stirred at 80 ° C. for 20 hours under an argon atmosphere. The reaction mixture was then cooled to room temperature, diluted with EtOAc, and extracted with brine, aqueous NaHCO ₃ (2 ×), and brine. The organic layer was dried over anhydrous MgSO ₄ and concentrated to dryness. The carbamate-ester product was isolated (180 mg) after flash column chromatography using 20% to 30% EtOAc in hexane. After removal of the Boc protecting group with 4N HCl in dioxane for 30 minutes, aniline hydrochloride was isolated.
Example 26
4- (2-methoxycarbonyl-4-methyl-thiazol-5-yl) -phenyl-ammonium chloride:

To a solution of 2-amino-4-methylthiazole (7.90 g, 69 mmol) in Et ₂ O (70 ml) at 15 ° C., Br ₂ was slowly added over a period of 30 minutes with vigorous stirring. The resulting solid material was filtered and recrystallized with EtOH. The crystalline product was filtered and dried in vacuo to give the 5-bromo derivative as the HBr salt (10.3 g). The product was then dissolved in a solution of CuSO ₄ (11.4 g) and NaBr (9.9 g) in H ₂ O (115 ml) and H ₂ SO ₄ (5M, 360 ml) was added at 0 ° C. A solution of NaNO ₂ (6.10 g in 20 ml H ₂ O) was then added dropwise to the reaction mixture over a period of 25 minutes, keeping the temperature below 3 ° C. The reaction mixture was stirred at 3 ° C. for 20 minutes and then at room temperature for 1 hour. The reaction mixture was diluted with brine (280 ml) and extracted with Et ₂ O (3 × 300 ml). The ether layers were combined and washed with a saturated aqueous solution of sodium thiosulfate to remove unreacted Br ₂ , dried over anhydrous MgSO ₄ and filtered through a pad of silica gel (about 200 ml). The solvent was evaporated and the desired product was isolated by distillation (boiling point at 15 mm Hg = 80-81 ° C.).
A solution of the dibromo intermediate (500 mg, 1.94 mmol) in hexane (5 ml) was added to a cold solution of n-BuLi (−70 ° C.) (2.2 M in hexane, 870 μL) and diluted with 10 ml of hexane. The reaction was stirred at −70 ° C. for 1 hour and then added to CO ₂ (s). The mixture was partitioned between H ₂ O and Et ₂ O. The aqueous layer was acidified with 1N HCl (pH˜2), extracted with EtOAc (2 ×), dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The residue is redissolved in MeOH / DCM, treated with CH ₂ N ₂ (until the solution remains yellow), evaporated to dryness to give the desired 5-bromo-4-methylthiazole-2-carboxylate ester in yellow Obtained as a solid (230 mg). This product was Suzuki cross-coupled with N-Boc protected 4-aminophenylboronic acid as previously described (Example 25) to form building block 5- (4-amino-phenyl) -4-methyl-thiazole. -2-Carboxylate methyl ester was obtained. The product was treated with 4N HCl in dioxane for 30 minutes to remove the Boc protecting group to give the desired compound.
Example 27
(E) -3- (4-Amino-phenyl) -2-methyl-acrylic acid methyl ester:

α-Methyl-4-nitrocinnamic acid (53 mg, 0.25 mmol) was dissolved in EtOAc and MeOH and a solution of CH ₂ N ₂ in Et ₂ O was added until a persistent yellow color was observed. Two drops of AcOH were added to destroy excess CH ₂ N ₂ . The mixture was diluted with EtOAc and the organic layer was washed with H ₂ O, aqueous NaOH (1N) and brine, dried over anhydrous MgSO ₄ and concentrated to dryness. The residue was redissolved in EtOH (2 ml), SnCl ₂ .2H ₂ O (289 mg, 1.28 mmol) was added and the reaction mixture was heated to reflux for 1 hour. The mixture was cooled to room temperature, diluted with EtOAc, and quenched by the addition of saturated aqueous NaHCO ₃ solution. The organic layer was separated, washed with brine, dried over anhydrous MgSO ₄ and concentrated to dryness to give the title compound (40 mg) as a yellow solid.
Example 28
4-((E) -2-methoxycarbonyl-vinyl) -3-methyl-phenyl-ammonium chloride:

4-Amino-2-methylcinnamic acid (0.090 g, 0.51 mmol) and NaOH (1M, 1.1 ml, 1.1 mmol) were dissolved in dioxane (4 ml) and Boc ₂ O (117 mg, 0.53 mmol) was added and the The mixture was stirred at room temperature for 15 hours. The reaction mixture was partitioned between EtOAc and H ₂ O and the pH of the aqueous layer was adjusted to basic using 1N NaOH and extracted with EtOAc (3 ×). The aqueous layer was then acidified to pH ˜2 and extracted with EtOAc (3 ×). The new organic layers were combined, washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated to give an orange gum (118 mg). The crude Boc-protected 4-amino-2-methylcinnamic acid was redissolved in EtOAc and a solution of CH ₂ N ₂ in Et ₂ O was added until a persistent yellow color was observed. A few drops of AcOH were added to destroy excess CH ₂ N ₂ and the reaction mixture was washed with 10% aqueous HCl, saturated NaHCO ₃ and brine, dried over anhydrous MgSO ₄ , filtered and concentrated , Dried. Purification by flash column chromatography using 10% EtOAc in hexane as eluent isolated the Boc-protected methyl ester as a yellow solid (36 mg). Finally, after acid treatment with HCl in dioxane as previously described, the Boc protecting group was removed to give the title compound.
Example 29
5-Amino-1-methyl-1H-indole-2-carboxylic acid ethyl ester

Ethyl ester of 5-nitroindole-2-carboxylic acid (0.300 g, 1.28 mmol) was dissolved in anhydrous DMF (6 ml) and NaH (0.078 g, 60%, 1.92 mmol) was added. The reaction was stirred at room temperature for 20 minutes, then MeI (160 μL, 2.56 mmol) was added and stirring was continued for 3 hours. The reaction was quenched by the addition of aqueous NaHCO ₃ (about 1%) while stirring vigorously. The resulting brown solid (0.096 g) was filtered and dried in air overnight.
The N-methylnitro derivative (196 mg, 0.79 mmol) was then dissolved in DMF (4 ml), H ₂ O (400 μL) and SnCl ₂ .2H ₂ O (888 mg, 3.95 mmol) were added and the mixture was heated at 60 ° C. Stir for 3 hours. The mixture was then partitioned between 10% aqueous NaHCO ₃ and EtOAc and stirred vigorously. The aqueous layer was extracted again with EtOAc and the combined EtOAc layers were washed with brine, dried over anhydrous MgSO ₄ and concentrated to dryness. The residue was purified by flash column chromatography using a 1: 1 ratio of EtOAc / hexane as eluent to give pure 5-aminoindole derivative (118 mg).
N-alkylation of 5-nitroindole-2-carboxylate with other alkylating agents (eg, EtI, propargyl bromide, benzyl bromide) under the conditions described above corresponds to 5-amino-1-alkyl-1H— Indole-2-carboxylate was produced.
Example 30
5-{[1- (4-Amino-1-t-butoxycarbonyl-piperidin-4-yl) -methanoyl] -amino} -1-methyl-1H-indole-2-carboxylic acid ethyl ester:

Amine from Example 29 (70 mg, 0.32 mmol), N-Fmoc-amino- (4-N-Boc-piperidinyl) carboxylic acid (150 mg, 0.32 mmol), HATU (139 mg, 0.35 mmol) in DMF (2 ml) A solution of HOAt (48 mg, 0.35 mmol) and collidine (155 mg, 1.28 mmol) was stirred at room temperature for 15 hours. The reaction mixture was diluted with EtOAc, washed with 1% aqueous citric acid (2 ×), saturated NaHCO ₃ (2 ×) and brine, dried over anhydrous MgSO ₄ , concentrated and dried to an orange solid (210 mg This was used in the next reaction without purification. A solution of crude acid (210 mg) in DMF (3 ml) and piperidine (95 ml, 0.95 mmol) was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness and purified by flash column chromatography using a solvent gradient from 50% EtOAc in hexane to 100% EtOAc as eluent to give the compound as a brown solid (110 mg). It was.
Example 31
5-{[1- (4-Amino-1-ethyl-piperidin-4-yl) -methanoyl] -amino} -1-methyl-1H-indole-2-carboxylic acid ethyl ester:

The 5-aminoindole derivative of Example 29 was coupled to N-Fmoc-amino- (4-N-Boc-piperidinyl) carboxylic acid as described in Example 30.
The Boc protecting group was removed in the usual way with 25% TFA in CH ₂ Cl ₂ and then the product was dissolved in EtOH (6 ml). AcOH (133 mg), acetaldehyde (33 mg, 0.74 mmol) and NaCNBH ₃ (23 mg, 0.37 mmol) were added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to remove most of the solvent and the residue was redissolved in EtOAc and washed with saturated NaHCO ₃ and brine. The organic layer was dried over anhydrous MgSO ₄ and concentrated to give the N-ethyl derivative as an orange solid.
This solid was dissolved in THF (2.5 ml), DBU (113 mg, 0.74 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated, the remaining residue was dissolved in EtOAc and the organic layer was washed with saturated NaHCO ₃ and brine. Further, the organic layer was extracted with 1N HCl and H ₂ O (2 ×), and the pH of the combined aqueous layer was adjusted to about 10 with 1N NaOH. The aqueous layer was then extracted with EtOAc (3 ×) and the combined organic layers were washed with brine, dried over anhydrous MgSO ₄ and concentrated to dryness to give the title amine derivative (44 mg).
Example 32
(E) -3- (4-{[1- (3-Amino-piperidin-3-yl) -methanoyl] -amino} -phenyl) -acrylic acid ethyl ester:

According to an operation similar to that described in Example 31, the commercially available N-Fmoc-amino- (3-N-Boc-piperidinyl) carboxylic acid was coupled to the ethyl ester of 4-aminocinnamic acid and the Fmoc protecting group To give the title compound of Example 32 in racemic form.
Also, the racemic starting material, N-Fmoc-amino- (3-N-Boc-piperidinyl) carboxylic acid, was used as a chiral carrier (Chillacel OD, 10 microns, 2.00) using 35% H ₂ O in MeCN as the eluent. Preparative HPLC with cm (inner diameter) x 25 cm) could be divided into two enantiomers.
Example 33
General procedure for coupling α, α-disubstituted amino acids to aromatic amines
(E) -3- [4- (2-Amino-2-methyl-propanoylamino) -phenyl] -acrylic acid ethyl ester:

Adapting the procedure described by ES Uffelman et al. (Org. Lett. 1999, 1, 1157), 2-aminoisobutyric acid was converted to the corresponding amino acid chloride hydrochloride. 2-Oxazolidinone (12.30 g, 0.141 mmol) was dissolved in MeCN (150 ml) and phosphorus pentachloride (49.02 g, 0.235 mol, 1.7 eq) was added in one portion. The homogeneous mixture was stirred at room temperature for 24 hours. 2-Aminoisobutyric acid (14.55 g, 0.141 mol) was added and the suspension was stirred at room temperature for 48 hours. The desired acid chloride hydrochloride was collected by filtration, washed with MeCN and dried in vacuo.
The acid chloride (12.778 g, 80 mmol, 1.4 eq) was suspended in DCM (200 ml) and ethyl 4-aminocinnamate (11.045 g, 57.7 mmol, 1 eq) was added. Pyridine (7.01 ml, 86.6 mmol, 1.5 eq) was added dropwise and the mixture was stirred at room temperature for 3.5 hours. The reaction was then poured into a mixture of 1N NaOH (25 ml) and saturated aqueous NaHCO ₃ (100 ml) and extracted with EtOAc. The organic phase was washed with aqueous NaHCO ₃ solution, water and brine and dried over MgSO ₄ . The solvent was removed under reduced pressure to give the title compound as a white solid (15.96 g, 101% yield).
Example 34
(E) -3- (4-{[1- (1-Amino-cyclobutyl) -methanoyl] -amino} -phenyl) -acrylic acid ethyl ester:

Diethyl 1,1-cyclobutanedicarboxylate (20.00 g, 100 mmol) and KOH (6.60 g, 100 mmol) were refluxed in EtOH (100 ml) for 2 hours. After cooling to room temperature, the volatiles were removed under reduced pressure and the residue was partitioned between Et ₂ O and 4N HCl. The organic extract was washed with water and brine and dried over MgSO ₄ . The solvent was removed under reduced pressure to give the monoester as a clear oil (14.45 g, 84% yield).
The previous monoester (14.45 g, 84 mmol), Et ₃ N (14.1 ml, 100 mmol) and diphenylphosphoryl azide (24.05 g, 87.4 mmol) were dissolved in dry toluene (114 ml) and the mixture was dissolved at 80 ° C. Heated for 1 hour and further heated at 110 ° C. for 1 hour. Trimethylsilylethanol (9.94 g, 100 mmol) was added in one portion and the mixture was refluxed for 48 hours. The toluene was then removed under reduced pressure and the residue was dissolved in DCM. The solution was washed with water and brine and dried over MgSO ₄ . Concentration under reduced pressure gave a dark oil which was purified by passing it through a pad of silica gel using 30% EtOAc in hexane as eluent. The desired carbamate was obtained as a clear yellow liquid (21.0 g). The previous carbamate (1.50 g, 5.22 mmol) was dissolved in THF (5 ml) and 2N NaOH (5 ml) was added. The mixture was stirred at 70 ° C. for 1 hour. After dilution with water, the aqueous phase was washed with Et ₂ O to remove unreacted starting material. The aqueous phase was then acidified with KHSO ₄ and the product was extracted with EtOAc. The desired free carboxylic acid was obtained as an oil (1.25 g).
The previous acid (0.519 g, 2.0 mmol) was dissolved in DCM (10 ml). DIEA (1.39 ml, 8.0 mmol, 4 eq) was added followed by ethyl 4-aminocinnamate (0.573 g, 3.0 mmol, 1.5 eq) and HATU (1.143 g, 3.0 mmol, 1.5 eq). The mixture was stirred at room temperature for 3 days. The reaction was poured into TBME (100 ml) and the solution was washed successively with 10% aqueous citric acid (2 × 25 ml) and saturated aqueous NaHCO ₃ (25 ml) and dried over MgSO ₄ . The solvent was removed under reduced pressure and the residue was stirred with TFA (10 ml) for 30 minutes. The volatiles were then removed under reduced pressure and the residue was coevaporated twice with hexane. The crude product was dissolved in TBME (60 ml) and the solution was washed with 1N NaOH (2 × 25 ml). After drying (Na ₂ SO ₄ ), the volatiles were removed in vacuo to give the title compound as a light brown solid (0.500 g).
Example 35
Carbonic acid 3-[(S) -2-tert-butoxycarbonylamino-2- (2-amino-thiazol-4-yl) -ethyl] -1H-indol-5-yl ester tert-butyl ester:

(S) -5-hydroxytryptophan was converted to its bis-Boc derivative by the method of VF Pozdnev, Chem. Nat. Compd. (Engl.Transl.) 1982, 18 (1), 125, and this was converted as the free carboxylic acid. Isolated. This material (1.0377 g, 2.47 mmol) was dissolved in THF (5 ml), DIEA (0.645 ml, 3.7 mmol) was added and the mixture was cooled in ice. Isobutyl chloroformate (0.384 ml, 2.96 mmol) was added and the mixture was stirred at 0-5 ° C. for 18 hours. Then excess diazomethane (0.6M, 15 ml) in Et ₂ O was added and the mixture was stirred for 1 hour. Another portion of diazomethane (10 ml) was added and after 40 minutes the reaction was diluted with Et ₂ O (75 ml). The solution was washed successively with 10% aqueous citric acid (25 ml) and saturated aqueous NaHCO ₃ (25 ml) and dried (MgSO ₄ ). Volatiles were removed under reduced pressure and the residue was purified by flash chromatography using 40% EtOAc / hexanes. Diazomethyl ketone was obtained as a yellow foam (0.783 g).
The previous diazomethylketone was dissolved in EtOAc (10 ml) and the solution was cooled to -30 ° C. A solution of HBr in AcOH (48% w / w, 0.384 ml) was added dropwise over 60 minutes. The cold reaction mixture was then diluted with Et ₂ O (100 ml), washed successively with 10% aqueous citric acid (2 × 25 ml) and saturated aqueous NaHCO ₃ (25 ml) and dried (MgSO ₄ ). Volatiles were removed under reduced pressure and the residue co-evaporated with hexanes to give bromomethyl ketone as a white foam (0.870 g).
The previous bromomethyl ketone was reacted with thiourea (2 equivalents) in MeCN at room temperature for 18 hours. The solvent was then removed under reduced pressure and the residue was dissolved in minimal DMSO. This solution was added dropwise with stirring to a mixture of water (15 ml) and DIEA (0.2 ml). The resulting precipitate was collected by filtration, washed with water and dried to give the title compound.
This method is general and can be applied to the preparation of other 2-alkyl and 2-alkylaminothiazole derivatives by reacting appropriate thioamide or thiourea derivatives with the bromomethyl ketone compounds described above.
Example 36
Carbonic acid 3-((S) -2-tert-butoxycarbonylamino-2-thiazol-4-yl-ethyl) -1H-indol-5-yl ester tert-butyl ester:

To a stirred suspension of P ₂ S ₅ (0.89 g, 2.0 mmol) in dry dioxane (5 ml) was added dry formamide (433 μL, 10.9 mmol). The mixture was heated at 90 ° C. for 2.5 hours (requiring occasional grinding to maintain free suspension). The suspension was cooled to room temperature, the solid was filtered off, and the bromoketone from Example 29 (0.5 mmol) was added to the filtrate. The solution was heated to 80 ° C. for 2 hours, then diluted with EtOAc (25 ml) and washed with 5% aqueous citric acid (2 × 20 ml), 5% aqueous sodium bicarbonate (2 × 10 ml) and brine. After drying (MgSO ₄ ) and removing the solvent under reduced pressure, the title compound was obtained.
Example 37 (Entry 2050)
General procedure for coupling 5- or 6-indolecarboxylic acids to α, α-disubstituted aminoamides
(E) -3- [4- (2-{[1- (3-cyclohexyl-2-furan-3-yl-1H-indol-6-yl) -methanoyl] -amino} -2-methyl-propanoyl Amino) -phenyl] -acrylic acid:

Indolecarboxylic acid derived from the methyl ester of Example 3 (0.050 g, 0.16 mmol), the aminoamide derivative of Example 33 (0.053 g, 0.019 mmol, 1.2 eq) and HATU (0.122 g, 0.32 mmol, 2 eq). Dissolved in DMSO (1 ml). DIEA (0.14 ml, 0.8 mmol, 5 eq) was added. The mixture was stirred at room temperature for 1 hour and then treated with 2.5N NaOH (0.3 ml) at 50 ° C. for 1 hour to effect hydrolysis of the cinnamate ester functionality. The mixture was then acidified to pH 1 with TFA and the title compound was isolated by preparative reverse phase HPLC (0.033 g).
Example 38 (entry 1010)
General procedure for coupling thiazole derivatives (Examples 35, 36) to 6-indolecarboxylic acids:

The thiazole derivative of Example 35 was deprotected by stirring with 4N HCl in dioxane and derived from the methyl ester of Example 3 using TBTU / DIEA in DMSO as described in Example 37. To the 6-indolecarboxylic acid prepared. After coupling, the title compound was isolated directly by preparative reverse phase HPLC.
Example 39
3-cyclohexyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carboxylic acid [1- (4-amino-phenylcarbamoyl) -1-methyl-ethyl] -amide (entry 2072):

The aminoamide derivative prepared from α-aminoisobutyryl chloride and 4-nitroaniline according to the procedure of Example 33 was coupled to the indole derivative of Example 9 in the usual manner (Example 37).
The nitro derivative was hydrogenated in MeOH for 5 hours (1 atm H ₂ gas, 10% Pd / C) to give the title compound after purification by preparative reverse phase HPLC.
Example 40
(E) -3- (4-{[1- (1-{[1- (2-carbamoyl-3-cyclopentyl-1-methyl-1H-indol-6-yl) -methanoyl] -amino} -cyclopentyl) -Methanoyl] -amino} -phenyl) -acrylic acid:

An amine (55.7 mg, prepared by adapting the acid aldehyde (50 mg, 0.184 mmol) and the procedure described in Example 33, derived from the saponification of the ester aldehyde of Example 16 in CH ₂ Cl ₂ . To a mixture of 0.184 mmol) HATU (84 mg, 0.221 mmol) and DIEA (128 μL, 0.738 mmol) were added in succession. The reaction mixture was stirred at room temperature overnight and then concentrated. The residue was dissolved in EtOAc and washed successively with 10% aqueous citric acid (2X), saturated aqueous NaHCO ₃ , water and then brine. After normal treatment (MgSO ₄ , filtration and concentration), the residue was subjected to flash chromatography (2 cm, 35% AcOEt-hexane) to give the desired amide-aldehyde derivative (83.5 mg, 0.150 mmol, 81.5% yield). .
The aldehyde (87 mg, 0.157 mmol) in a mixture of tert-butanol (2 ml) and 2-methyl-2-butene (1.2 ml) at 0 ° C. was added to phosphate buffer (NaH ₂ PO in 600 μL of water). _{4 A} freshly prepared solution of sodium chlorite (141.6 mg, 1.57 mmol) in 216 mg, 1.57 mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes and then brine was added. The mixture was extracted with EtOAc (2X) and the combined organic layers were washed successively with 0.5N aqueous solution and brine. After usual treatment (MgSO ₄ , filtration and concentration), the desired crude acid was isolated as a white solid (82.6 mg, 92.3% yield).
To the acid (15 mg, 0.0275 mmol) in DMF at 0 ° C., DIEA (7.2 μL, 0.0413 mmol) and isobutyl chloroformate (10.7 μL, 0.0413 mmol) were added sequentially. The reaction mixture was stirred at this temperature for 30 minutes and then ammonium hydroxide (7.5 μL, 0.056 mmol) was added. After the addition, the mixture was gradually warmed to room temperature and stirred overnight. 1N NaOH aqueous solution was added (275 μL, 0.275 mmol) and the reaction mixture was heated at 60 ° C. for 1.5 h. Finally, glacial acetic acid was added to decompose excess hydroxide and the mixture was purified by HPLC. After lyophilization, the desired amide was isolated as a white solid (2.6 mg, 0.005 mmol, 18% yield).
Other 2-carboxamide derivatives were prepared in a similar manner by replacing ammonia with the desired amine.
Example 41
(E) -3- [4-((E) -3-{[1- (3-Cyclopentyl-1-methyl-2-pyridin-2-yl-1H-indol-6-yl) -methanoyl] -amino } -3-Methyl-buten-1-yl) -phenyl] -acrylic acid:

3-Cyclopentyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carboxylic acid (0.100 g, 0.31 mmol), 2-amino-2-methyl-1-propanol (0.028 g, 0.31 mmol) And HATU (0.154 g, 0.41 mmol) were dissolved in DMSO (5 ml). To this mixture was added DIEA (0.22 ml, 1.2 mmol) and the solution was stirred at room temperature for 3 hours. The reaction mixture was poured into EtOAc (100 ml) and the solution was washed successively with saturated aqueous NaHCO ₃ solution (2 × 25 ml) and brine (25 ml) and dried over anhydrous MgSO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (using 60-70% EtOAc in hexanes) to give the primary alcohol intermediate as a yellow oil (0.048 g). This product was dissolved in CH ₂ Cl ₂ (2 ml), Dess-Martin periodate (0.063 g, 0.15 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with CH ₂ Cl ₂ (100 ml), the organic layer was dried over anhydrous MgSO ₄ and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (using 60% EtOAc in hexane) to give the aldehyde intermediate (0.011 g).
Slowly add diazomethane to a solution of 4-methylcinnamic acid (3.0 g, 18.5 mmol) in CH ₃ OH / CH ₂ Cl ₂ (5 ml / 15 ml) until the yellow color persists (indicating the presence of excess diazomethane) did. The solution was evaporated to dryness under reduced pressure and the residue was redissolved in CCl ₄ (15 ml). N-bromosuccinimide (3.62 g, 20.4 mmol) and AIBN (0.304 g, 1.85 mmol) were added and the mixture was stirred at reflux for 3 hours. The solution was then cooled to room temperature and filtered. The organic layer was washed with aqueous NaOH (0.5N, 2 × 50 ml) and water (50 ml), dried over anhydrous MgSO ₄ and filtered. The solvent was removed in vacuo and the residue was purified by flash column chromatography (0-40% EtOAc in hexanes) to give the bromide intermediate as a white solid (2.4 g). This product was dissolved in (EtO) ₃ P (37.7 ml, 220 mmol) and heated at 160 ° C. to reflux. The resulting ethyl bromide was collected in a Dean-Stark distillation apparatus over a 2.5 hour period. The reaction mixture was condensed in vacuo to give a yellow solid, which was then purified by flash column chromatography (70-100% EtOAc in hexanes) to give the phosphonate as a white solid (1.9 g).
A solution of phosphonate (20 mg, 0.06 mmol) and NaH (60%, 3.5 mg, 0.087 mmol) in anhydrous THF (300 μL) was stirred at room temperature for 30 minutes. A solution of the aldehyde intermediate (11 mg, 0.029 mmol) in THF was added and stirring was continued for 4 hours. After that period, aqueous NaOH (2.5N, 50 μL) was added and the mixture was stirred at 40 ° C. for 15 hours. The mixture was acidified with glacial acetic acid (ca. 1 ml), concentrated and purified by reverse phase HPLC to give the title compound (3.7 mg) as a yellow solid.
Example 42
(Z) -3- [2- (1-Amino-cyclopentyl) -1H-benzimidazol-5-yl] -acrylic acid methyl ester:

Diazomethane was slowly added to a solution of 4-chloro-3-nitrocinnamic acid in CH ₃ OH / CH ₂ Cl ₂ until the yellow color persisted (indicating the presence of excess diazomethane). The solution was evaporated to dryness under reduced pressure and the residue was dissolved in DMSO. The solution was heated to 140 ° C. and ammonia gas was bubbled over a period of 4 hours. The mixture was cooled to room temperature, degassed with N ₂ and poured onto ice. The resulting precipitate was filtered, washed with cold water and dried in vacuo for 16 hours to give crude 4-amino-3-nitrocinnamic acid ester as a yellow solid (2.05 g). The solid was dissolved in ethanol (40 ml), SnCl ₂ dihydrate (9.91 g, 43.9 mmol) was added and the reaction mixture was heated to reflux for 4 hours. The solution was concentrated to remove most of the ethanol, diluted with EtOAc, and saturated aqueous NaHCO ₃ was added slowly. The mixture was stirred for 20 minutes and the organic layer was extracted with brine, dried over anhydrous Na ₂ SO ₄ and evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (using 50% to 70% EtOAc in hexanes) to give the diamino intermediate as a yellow solid (1.03 g).
A portion of 3,4-diaminocinnamate ester (186 mg, 0.970 mmol) and N-Boc-1-aminocyclopentane-1-carboxylic acid (222 mg, 0.970 mmol) were coupled in the presence of HATU / DIEA ( The resulting amide product was dehydrated by heating at 65 ° C. in a solution of acetic acid (4 ml). The reaction residue was purified by reverse phase HPLC to give N-Boc protected (Z) -3- [2- (1-amino-cyclopentyl) -1H-benzimidazol-5-yl] -acrylic acid ethyl ester.
The Boc protecting group is removed in the usual manner with 4N HCl in dioxane to give (Z) -3- [2- (1-amino-cyclopentyl) -1H-benzimidazol-5-yl] -acrylic acid ethyl ester. Obtained as a yellow foam (200 mg).
Example 43
2-Amino-3H-benzimidazole-5-carboxylic acid:

A solution of cyanogen bromide (5M, 1.44 ml, 7.22 mmol) was slowly added to a suspension of 3,4-diaminobenzoate (1.0 g, 6.02 mmol) in water (10 ml). The mixture was stirred at room temperature for 24 hours. An aqueous solution of Na ₂ CO ₃ (10%) was added slowly until the product precipitated as a brown solid (890 mg).
Example 44
5-Amino-3-iodo-1H-indole-2-carboxylic acid ethyl ester:

Ethyl 5-nitroindole-2-carboxylate (1.00 g, 4.27 mmol) was dissolved in DMF (15 ml), KOH (0.84 g, 14.9 mmol) was added and the mixture was stirred at room temperature for 10 minutes. Iodine (1.084 g, 4.27 mmol) was added and stirring was continued for 3 hours. The reaction mixture was poured into a solution of water (150 ml) containing NaHSO ₃ (1 g) and concentrated NH ₄ OH (2.5 ml). The resulting precipitate was filtered, washed with water and dried to give the 3-iodo intermediate as a beige solid (1.49 g). A portion of this solid (503 mg, about 1.4 mmol) was dissolved in ethanol (15 ml), SnCl ₂ dihydrate (1.58 g, 6.99 mmol) was added, and the reaction mixture was heated to reflux for 4 hours. . The solution was concentrated to remove most of the ethanol, diluted with EtOAc, and saturated aqueous NaHCO ₃ was added slowly until pH = 8-9. The mixture was stirred for 20 minutes and the organic layer was extracted with brine, dried over anhydrous Na ₂ SO ₄ and evaporated to dryness under reduced pressure. The residue (431 mg of a brown solid) contains the desired product 5-amino-3-iodo-1H-indole-2-carboxylic acid ethyl ester of reasonable purity to be used in the synthesis of the inhibitor without further purification. It was.
Example 45
(E) -3- (4-{[1-((S) -3-{[1- (3-Cyclopentyl-1-methyl-2-pyridin-2-yl-1H-indol-6-yl)- Methanoyl] -amino} -1-methyl-pyrrolidin-3-yl) -methanoyl] -amino} -phenyl) -acrylic acid:

3-Cyclopentyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carboxylic acid (0.197 mg, 0.589 mmol), appropriate amine (0.170 g, 0.420 mmol) and HATU (0.320 g, 0.840 mmol) ) Was dissolved in DMSO (4 ml). To this mixture was added Et ₃ N (0.300 ml, 2.15 mmol) and the solution was stirred at room temperature for 5 hours. The reaction mixture was poured into EtOAc (100 ml) and the solution was washed successively with 1% aqueous citric acid solution (2 × 25 ml), saturated aqueous NaHCO ₃ solution (2 × 25 ml) and brine (25 ml) and dried over anhydrous MgSO _4. It was. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (using a 1: 1 ratio of hexane / EtOAc) to give the intermediate product as a slightly colored foam (280 mg). The product was stirred in 4N HCl in dioxane (3.0 ml) for 1 hour (to remove the Boc protecting group) and then all volatile components were removed in vacuo.
Part of the residue (41 mg, 0.060 mmol) was dissolved in ethanol (2 ml), acetic acid (31 mg, 0.530 mmol) was added, 37% aqueous formaldehyde (15 μL, ca. 0.2 mmol) and NaBH ₃ CN (5.6 mg, 0.090 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure, the residue was redissolved in DMSO (1 ml), aqueous NaOH (2.5 N, 230 μL, 0.58 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified by the addition of acetic acid (ca. 1 ml) and purified by C18 reverse phase preparative HPLC to give the final product as a light yellow solid (11 mg).

Example 46: Inhibition of NS5B RNA-dependent RNA polymerase activity The compounds of the invention were tested for their inhibitory activity against hepatitis C virus RNA-dependent polymerase (NS5B) according to the following assay.
The substrate is a 12 nucleotide RNA oligo-uridylate (or oligo-uridine-monophosphate) (oligo-U) primer modified with biotin at the free 5′C position;
A heterogeneous length (1000-10000 nucleotides) complementary poly-adenylate (or adenosine monophosphate) (polyA) template; and
UTP- [5,6 ³ H].
Polymerase activity is measured as the incorporation of UMP- [5,6 ³ H] into the extended strand from the oligo-U primer. ³ H-labeled reaction products are captured by streptavidin-coated SPA-beads and quantified by top count.
All solutions were made from DEPC treated milli-Q water (2 ml of DEPC was added to 1 liter of milli-Q water and the mixture was shaken vigorously to dissolve DEPC and then autoclaved at 121 ° C. for 30 minutes).
Enzyme: Full length HCV NS5B (SEQ ID NO: 1) was purified as an N-terminal hexa-histidine fusion protein from baculovirus infected insect cells. The enzyme can be stored at −20 ° C. in a storage buffer (see below). Under these conditions it was found to maintain activity for at least 6 months.
Substrate: biotinylated oligo -U ₁₂ primers, poly (A) template, and UTP- a [5, 6 ³ H] were dissolved in water. These solutions can be stored at -80 ° C.

Assay buffer: 20 mM Tris-HCl pH 7.5
5 mM MgCl ₂
25 mM KCl
1mM EDTA
1mM DTT
NS5B storage buffer: 0.1 μM NS5B
25 mM Tris-HCl pH 7.5
300 mM NaCl
5mM DTT
1mM EDTA
0.1% n-dodecyl maltoside
30% Glycerol Test Compound Cocktail: Just prior to the assay, test compounds of the present invention were dissolved in assay buffer containing 15% DMSO.
Substrate cocktail: Immediately prior to the assay, the substrate was mixed in assay buffer to the following concentrations:

酵素カクテル：アッセイの直前に、RNAポリメラーゼ(NS5B)カクテルを下記の仕様にアッセイ緩衝液中で調製した。

Enzyme cocktail: Immediately prior to the assay, an RNA polymerase (NS5B) cocktail was prepared in assay buffer to the following specifications.

protocol:
The assay reaction is 20 μL of test compound cocktail;
20 μL substrate cocktail; and 20 μL enzyme cocktail
It was performed in micro full O ^TM white "U" bottom plate by adding sequentially (Dynatech ^TM # 7105) (final in assay [NS5B] = 10 nM; final in assay [n- dodecyl maltoside] = 0.33%; final DMSO in assay = 5%).
The reaction was incubated at room temperature for 1.5 hours. Stop solution (20 μL; 0.5 M EDTA, 150 ng / μl tRNA) followed by 30 μl streptavidin coated PVT beads (20 mM Tris-HCl, pH 7.5, 25 mM KCl, 8 mg / ml in 0.025% NaN ₃ ) Was added. The plate was then shaken for 30 minutes. A solution of CsCl (70 μL, 5M) was added to bring the CsCl concentration to 1.95M. The mixture was then left for 1 hour. The beads were then counted on a Hewlett Packard TopCount ^™ instrument using the following protocol.
Data format: Count / min Scintillator: Liquid / plast energy range: Low efficiency Format: Normal area: 0-50
Count delay: 5 minutes Count time: 1 minute Expected result: 6000cpm / well
200 cpm / well enzyme-free control.
Based on the results at 10 different concentrations of the test compound, standard concentration-% inhibition curves were plotted and analyzed to determine the IC ₅₀ for the compounds of the invention. For certain compounds, the IC ₅₀ was estimated from two points.

Example 47 Specificity of NS5B RNA-Dependent RNA Polymerase Inhibition Poliovirus RNA-dependent RNA polymerase and a compound of the invention in the format described for HCV polymerase, except that another polymerase is used instead of HCV NS5B polymerase The inhibitory activity against bovine thymus DNA-dependent RNA polymerase II was tested.
Example 48: Cell-based HCV RNA replication assay Cell culture Huh7 cells that stably maintain a subgenomic HCV replicon were established as previously described (Lohman et al., 1999 Science 285: 110-113), S22. Called 3 cell line. S22.3 cells are maintained in Dulbecco's modified Earl's medium (DMEM) (standard medium) supplemented with 10% FBS and 1 mg / ml neomycin. During the assay, DMEM medium supplemented with 10% FBS, containing 0.5% DMSO and lacking neomycin was used (assay medium). Sixteen hours prior to compound addition, S22.3 cells are trypsinized and diluted to 50000 cells / ml in standard medium. Dispense 200 μL (10000 cells) into each well of a 96 well plate. The plates were then incubated with 5% CO ₂ at 37 ° C. until the next day.
Reagents and substances:

Test Compound Preparation 10 μL of test compound (in 100% DMSO) was added to 2 ml of assay medium for a final DMSO concentration of 0.5% and the solution was sonicated for 15 minutes and filtered through a 0.22 μM Millipore filter unit. 900 μl was transferred to row A of a polypropylene deep-well titer plate. Columns BH contain 400 μl aliquots of assay medium (containing 0.5% DMSO) and are used to prepare serial dilutions (1/2) by transferring 400 μl from column to column (compounds Not included in column H).
Application of test compound to cells Cell culture medium was aspirated from 96-well plates containing S22.3 cells. 175 μL of assay medium containing the appropriate dilution of test compound was transferred from each well of the compound plate to the corresponding well of the cell culture plate (row H was used as an “uninhibited control”). Cell culture plates were incubated with 5% CO ₂ at 37 ° C. for 72 hours.

Extraction of total cellular RNA
After a 72 hour incubation period, total cellular RNA was extracted from S22.3 cells in a 96-well plate using the RNeasy 96 kit (Qiagen®, RNeasy Handbook. 1999). Briefly, assay medium was completely removed from the cells and 100 μL of RLT buffer (Qiagen®) containing 143 mM β-mercaptoethanol was added to each well of a 96-well cell culture plate. The microplate was gently shaken for 20 seconds. Then 100 μL of 70% ethanol was added to each microplate well and mixed by pipetting. Lysate was removed and applied to the wells of RNeasy 96 (Qiagen®) plates placed on top of the Qiagen® square-well block. The RNeasy96 plate was sealed with tape and the square-well block containing the RNeasy96 plate was loaded into the holder and placed in the rotor bucket of a 4K15C centrifuge. Samples were centrifuged at 6000 rpm (about 5600 × g) for 4 minutes at room temperature. The tape was removed from the plate and 0.8 ml of Buffer RW1 (Qiagen® RNeasy96 kit) was added to each well of the RNeasy96 plate. The RNeasy 96 plate was sealed with a new piece of tape and centrifuged at 6000 rpm at room temperature for 4 minutes. The RNeasy96 plate was placed on another clean square-well block, the tape was removed, and 0.8 ml of buffer RPE (Qiagen® RNeasy96 kit) was added to each well of the RNeasy96 plate. The RNeasy 96 plate was sealed with a new piece of tape and centrifuged at 6000 rpm at room temperature for 4 minutes. The tape was removed and an additional 0.8 ml of buffer RPE (Qiagen® RNeasy96 kit) was added to each well of the RNeasy96 plate. The RNeasy 96 plate was sealed with a new piece of tape and centrifuged at 6000 rpm for 10 minutes at room temperature. The tape was removed and the RNeasy 96 plate was placed on a rack containing 1.2 ml collection microtubules. RNA was eluted by adding 50 μL of RNase-free water to each well and the plate was sealed with a new piece of tape and incubated for 1 minute at room temperature. The plate was then centrifuged at 6000 rpm for 4 minutes at room temperature. The elution step was repeated with 50 μl of a second volume of RNase free water. Microtubules containing total cellular RNA are stored at -70 ° C.

Quantification of total cellular RNA RNA was quantified with the Storm® system (Molecular Dynamics®) using the Ribogreen® RNA quantification kit (Molecular Probes®). Briefly, Ribogreen reagent was diluted 200-fold in TE (10 mM Tris-HCl pH = 7.5, 1 mM EDTA). In general, 50 μL of reagent was diluted in 10 ml of TE. A standard curve of ribosomal RNA is diluted to 2 μg / ml in TE, and then a predetermined amount (100, 50, 40, 20, 10, 5, 2, and 0 μL) of ribosomal RNA solution is added to a new 96-well plate (Costar # 3997) and supplemented the volume to 100 μL with TE. In general, column 1 of a 96 well plate is used for the standard curve and another well is used for the RNA sample to be quantified. 10 μL of each RNA sample to be quantified was transferred to the corresponding well of a 96 well plate and 90 μL of TE was added. A volume (100 μL) of diluted ribogreen reagent was added to each well of a 96-well plate, incubated at room temperature for 2-5 minutes, protected from light (10 μL of RNA sample in a final volume of 200 μL was Resulting in a 20-fold dilution). The fluorescence intensity of each well was measured with a Storm® system (Molecular Dynamics®). A standard curve was generated based on known amounts of ribosomal RNA and the resulting fluorescence intensity. The RNA concentration in the experimental sample was measured from a standard curve and corrected for a 20-fold dilution.
Reagents and substances:

Real-time RT-PCR
Real-time RT-PCR was performed on the ABI Prism 7700 sequence detection system using a Takman EZ RT-PCR kit (from Perkin-Elmer Applied Biosystems®). RT-PCR can be performed with HCV by using the same Taqman technology (Roche Molecular Diagnostics Systems) as previously described (Martell et al., 1999. J. Clin. Microbiol. 37: 327-332). Optimized for RNA 5'IRES quantification. The system makes use of the 5'-3 'nucleolytic activity of amplitac DNA polymerase. Briefly, the method utilizes a dual-labeled fluorogenic hybridization probe (PUTR probe) that specifically anneals to the template between PCR primers (primers 8125 and 7028). The 5 ′ end of the probe contains a fluorescent reporter (6-carboxyfluorescein [FAM]) and the 3 ′ end contains a fluorescent quencher (6-carboxytetramethylrhodamine [TAMRA]). The emission spectrum of the FAM reporter was suppressed by the intact hybridization probe quencher. Nuclease degradation of the hybridization probe releases the reporter, resulting in increased fluorescence emission. The ABI Prism 7700 sequence detector continuously measured the increase in fluorescence emission during PCR amplification, so that the amplification product was directly proportional to the signal. Amplification plots were analyzed early in the reaction at a time point corresponding to the log phase of product accumulation. The point corresponding to the specific detection threshold for the increase in fluorescence signal associated with the exponential growth of the PCR product for the sequence detector was defined as the cycle threshold (C _T ). _CT value is inversely proportional to the amount of input HCV RNA. As a result, in the same PCR conditions, the larger the starting concentration of HCV RNA, C _T is low. By plotted against standard dilution of each of the C _T known HCV RNA concentration, it made a standard curve automatically by ABI Prism 7700 detection system. A reference sample for the standard curve is placed on each RT-PCR plate. HCV replicon RNA was synthesized in vitro (by T7 transcription), purified and quantified by OD ₂₆₀ . Considering that this RNA is 1 μg = 2.15 × 10 ¹¹ RNA copies, dilute to have 10 ⁸ , 10 ⁷ , 10 ⁶ , 10 ⁵ , 10 ⁴ , 10 ³ or 10 ² genomic RNA copies / 5 μL. In addition, whole cell Huh-7 RNA was taken up by each dilution (50 ng / 5 μL). 5 μL of each reference standard (HCV replicon + Huh-7 RNA) was combined with 45 μL of reagent mix and used for real-time RT-PCR reaction.
Real-time RT-PCR reactions were set up for experimental samples purified in RNeasy 96 well plates by combining 5 μl of each total cellular RNA sample with 45 μL of reagent mix.
Reagents and substances

Reagent mix preparation:

Forward primer sequence (SEQ ID NO: 2): 5'-ACG CAG AAA GCG TCT AGC CAT GGC GTT AGT-3 '
Reverse primer sequence (SEQ ID NO: 3): 5'-TCC CGG GGC ACT CGC AAG CAC CCT ATC AGG-3 '
Note: These primers amplify a 256-nt region present within the 5 'untranslated region of HCV.
PUTR probe sequence (SEQ ID NO: 4): 6FAM -TGG TCT GCG GAA CCG GTG AGT ACA CC TAMRA
Template-free control (NTC): Use 4 wells as “NTC” on each plate. For these controls, 5 μl of water is added to the wells instead of RNA.
Thermal cycling conditions:
50 ° C for 2 minutes
60 ° C 30 minutes
95 ° C 5 minutes
95 ℃ 15 seconds (2 cycles with the process immediately below)
1 minute at 60 ℃
90 ℃ 15 seconds (40 cycles with the process immediately below)
1 minute at 60 ℃

After termination of the RT-PCR reaction, data analysis required setting of a threshold fluorescence signal for the PCR plate and a standard curve was generated by plotting Ct values against the RNA copy number used for each reference reaction. The Ct value obtained for the assay sample is used to interpolate RNA copy number based on a standard curve.
Finally, RNA copy number is normalized (based on ribogreen RNA quantification of total RNA extracted from cell culture wells) and expressed as genome equivalent [ge / μg] per μg total RNA.
RNA copy number [ge / μg] from each well of the cell culture plate was a measure of the amount of replicating HCV RNA in the presence of various concentrations of inhibitors. % Inhibition was calculated by the following formula.
100-[(ge / μg inhibitor) / (ge / μg control) × 100]
A nonlinear curve fit with Hill model was applied to the suppression-concentration data and 50% effective concentration (EC ₅₀ ) was calculated by using SAS software (Statistical Software System; SAS Institute (Cary, NC)).
In the following Tables 1-9, the following ranges apply:
IC ₅₀ : A = 10 μM-1 μM; B = 1 μM-500 nM; and C <500 nM
EC ₅₀ : A = 5 μM-500 nM; and B = <500 nM.

Sequence listing

Claims (54)

A compound represented by formula I, isomers, enantiomers, diastereoisomers, or tautomers thereof, or salts thereof.

[Where,
A is O, S, NR ¹ or CR ¹ , wherein R ¹ is selected from the group consisting of H and (C _1-6 ) alkyl;
----- represents a single bond or a double bond,
R ² is halogen, R ²¹ , OR ²¹ , SR ²¹ , COOR ²¹ , SO ₂ N (R ²² ) ₂ , N (R ²² ) ₂ , CON (R ²² ) ₂ , NR ²² C (O) R ²² or NR ²² C (O) NR ²² , wherein R ²¹ and each R ²² are independently H, (C _1-6 ) alkyl, haloalkyl, (C _2-6 ) alkenyl, (C _3-7 ) Cycloalkyl, (C _2-6 ) alkynyl, (C _5-7 ) cycloalkenyl, 6-membered or 10-membered aryl or Het, and R ²¹ and R ²² may be optionally substituted with R ²⁰ Or both R ²² are bonded together to form a 5-, 6- or 7-membered saturated heterocycle with the nitrogen to which they are attached;
B is NR ³ or CR ³ provided that one of A or B is CR ¹ or CR ^{3 wherein} R ³ is (C _3-7 ) cycloalkyl and (C _5-7 ) Selected from cycloalkenyl
K is CR ⁴ where R ⁴ is H;
L is CR ⁵ in which R ⁵ has the same definition as R ⁴ defined above;
M is N or CR ⁷ where R ⁷ has the same definition as R ⁴ defined above;
Y ¹ is O or S;
Z is N (R ^6a ) R ⁶ , wherein R ^6a is H and R ⁶ is (C _3-6 ) cycloalkyl, (C _2-6 ) alkenyl, 6-membered aryl, Het, ( C _1-6 ) alkyl-aryl, (C _1-6 ) alkyl-Het, wherein the cycloalkyl, alkenyl, aryl, Het, alkyl-aryl, or alkyl-Het are all optionally substituted with R ⁶⁰ Where R ⁶⁰ is 1 to 4 substituents selected from the following group:
a) (C _1-6 ) alkyl, C _3-7 spirocycloalkyl optionally containing 1 or 2 heteroatoms, or (C _2-6 ) alkenyl, wherein (C _1-6 ) alkyl, C _3-7 spirocycloalkyl and (C _2-6 ) alkenyl may be substituted with R ¹⁵⁰ ;
b) OR ¹⁰⁴ (wherein R ¹⁰⁴ is H or (C _1-6 ) alkyl, which alkyl may be substituted with R ¹⁵⁰ );
e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H or (C _1-6 ) alkyl, R ¹¹² is (C _1-6 ) alkyl or aryl, and the alkyl and aryl are substituted with R ¹⁵⁰ May be);
i) COR ^{127 where} R ¹²⁷ is (C _1-6 ) alkyl;
j) COOR ^{128 where} R ¹²⁸ is H;
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, aryl or Het, and the alkyl, aryl and Het may be substituted with R ¹⁵⁰ );
l) Aryl or Het (wherein the aryl and Het may be substituted with R ¹⁵⁰ );
Wherein R ¹⁵⁰ is 1 to 3 substituents selected from the following group:
a) (C _1-6 ) alkyl or (C _2-6 ) alkenyl (wherein said (C _1-6 ) alkyl or (C _2-6 ) alkenyl may be substituted with R ¹⁶⁰ );
e) NR ¹¹¹ R ^{112 where} R ¹¹¹ is H and R ¹¹² is H;
j) COOR ^{128 where} R ¹²⁸ is H; and
k) CONR ¹²⁹ R ^{130 where} R ¹²⁹ and R ¹³⁰ are independently hydrogen;
R ¹⁶⁰ is COOR ¹⁶¹ or CON (R ¹⁶² ) ₂ , wherein R ¹⁶¹ and each R ¹⁶² are independently hydrogen.
1 or 2 substituents selected from the group consisting of
Or Z is N (R ^6a ) R ⁶ where R ^6a is as defined above and R ⁶ is

And
In the formula, R ⁷ and R ⁸ are each independently H or (C _1-6 ) alkyl, and the alkyl may be optionally substituted with R ⁷⁰ , wherein R ⁷⁰ is
e) NR ¹¹¹ R ^{112 where} R ¹¹¹ is H or (C _1-6 ) alkyl and R ¹¹² is H or (C _1-6 ) alkyl;
R ⁷ and R ⁸ are covalently bonded together to form a second (C _3-7 ) cycloalkyl or a 4-, 5- or 6-membered heterocycle having one heteroatom selected from O, N, and S Forming a ring,
Y ² is O or S;
R ⁹ is H, or
R ⁹ is covalently bonded to either R ⁷ or R ⁸ to form a 5 or 6 membered heterocyclic ring,
Q is 6- or 10-membered aryl, Het or (C _1-6 ) alkyl-aryl, all of which are optionally R ¹⁰⁰ (where R ¹⁰⁰ is
1 substituent selected from halogen or cyano, or 1 to 4 substituents selected from the group consisting of:
a) (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _2-6 ) alkenyl or (C _2-8 ) alkynyl (these groups may be substituted with R ¹⁵⁰ );
b) OR ^{104 where} R ¹⁰⁴ is H;
d) SO ₂ N (R ¹⁰⁸ ) _{2 where} R ¹⁰⁸ is H;
e) NR ¹¹¹ R ¹¹² (wherein R ¹¹¹ is H or (C _1-6 ) alkyl and R ¹¹² is H or (C _1-6 ) alkyl),
f) NR ¹¹⁶ COR ^{117 where} R ¹¹⁶ and R ¹¹⁷ are each H or (C _1-6 ) alkyl;
h) NR ¹²¹ COCOR ^{122 where} R ¹²¹ is H and R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ (where R ¹²³ and each R ¹²⁴ are independently H or (C _{1 -6} alkyl) or R ¹²⁴ is OH);
j) COOR ^{128 where} R ¹²⁸ is H;
k) CONR ¹²⁹ R ^{130 where} R ¹²⁹ and R ¹³⁰ are independently H;
l) Het may be substituted with R ¹⁵⁰ ; wherein R ¹⁵⁰ is one substituent that is cyano, or one to three substituents selected from the group consisting of:
e) NR ¹¹¹ R ^{112 where} R ¹¹¹ is H and R ¹¹² is H;
i) COR ^{127 where} R ¹²⁷ is (C _1-6 ) alkyl;
j) tetrazole or COOR ^{128 where} R ¹²⁸ is H; and
k) CONR ¹²⁹ R ¹³⁰ (wherein R ¹²⁹ and R ¹³⁰ are independently H)
Or may be substituted with a salt or derivative thereof,
Het is a 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N, and S, or a 9-membered having 1 to 5 heteroatoms selected from O, N, and S Or defined as a 10-membered heterocycle,
R ²⁰ each
-Halogen, -OPO ₃ H, NO ₂ , cyano, azide, C (= NH) NH ₂ , C (= NH) NH (C _1-6 ) alkyl or C (= NH) NHCO (C _1-6 ) alkyl 1 to 4 substituents selected from
a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, C _3-7 spirocycloalkyl optionally containing one or two heteroatoms, (C _2-6 ) Alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl (all of which may optionally be substituted with R ¹⁵⁰ ),
b) OR ^{104 where} R ¹⁰⁴ is H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, wherein the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is Optionally substituted with R ¹⁵⁰ ),
c) OCOR ^{105 wherein} R ¹⁰⁵ is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het, the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is optionally R ¹⁵⁰ May be substituted),
d) SR ¹⁰⁸ , SO ₂ N (R ¹⁰⁸ ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ^{108 wherein} each R ¹⁰⁸ is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ^{108 of the above} are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6- or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het or heterocycle may be optionally substituted with R ¹⁵⁰ ),
e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ¹¹² is H, CN, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, COOR ¹¹⁵ or SO ₂ R ^{115 where} R ¹¹⁵ Is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or ( C _1-6 alkyl) Het), or both R ¹¹¹ and R ¹¹² are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-membered, 6-membered or 7-membered saturated complex. forms a ring, said alkyl, cycloalkyl, aryl, Het, (C _1-6 Alkyl) aryl or (C _1-6 alkyl) Het, or heterocycle being optionally substituted with R ^0.99 if ^{necessary), f) NR 116 COR 117} ( wherein, R ¹¹⁶ and R ¹¹⁷ are each H, ( C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _{1- 6} alkyl) Het, said (C _1-6) alkyl, (C _3-7) cycloalkyl, (C _1-6) alkyl - (C _3-7) cycloalkyl, aryl, Het, (C _{1- 6} alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- ( C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹¹⁸ is covalently bound to R ¹¹⁹ and they are bound Bonded to nitrogen to form a 5-, 6-, or 7-membered saturated heterocycle, or ^R119 and ^R120 are covalently bonded together, and bonded to the nitrogen to which they are bonded, 5-membered, 6-membered Or a 7-membered saturated heterocycle, the alkyl, cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _{1- 6} alkyl) Het or heterocycle being optionally substituted with R ^0.99 if necessary),
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ and R ¹²² are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ), respectively. Cycloalkyl, 6- or 10-membered aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het is optionally substituted with R ¹⁵⁰ , or R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ , wherein R ¹²³ and each R ¹²⁴ is independently H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), or both R ¹²⁴ are covalently bonded together to form a 5-membered, 6 Forming a 7-membered or 7-membered saturated heterocycle, Alkyl, cycloalkyl, alkyl - cycloalkyl, aryl, Het, optionally substituted with (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het and R ^0.99 by heterocycle necessary),
i) COR ^{127 wherein} R ¹²⁷ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het , (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is necessary ^Optionally substituted by R ¹⁵⁰ )
j) COOR ^{128 wherein} R ¹²⁸ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het , (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ¹²⁹ and R ¹³⁰ are covalently bonded together and they are bonded Combined with nitrogen to form a 5-, 6- or 7-membered saturated heterocycle, the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁵⁰ ), l) aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het (all of which are optionally R ¹⁵⁰ may be substituted)
1 to 4 substituents selected from
R ¹⁵⁰
-From halogen, OPO ₃ H, NO ₂ , cyano, azide, C (= NH) NH ₂ , C (= NH) NH (C _1-6 ) alkyl or C (= NH) NHCO (C _1-6 ) alkyl 1 to 3 selected substituents, or
a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, C _3-7 spirocycloalkyl optionally containing 1 or 2 heteroatoms, (C _2-6 ) Alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl (all of which may optionally be substituted with R ¹⁶⁰ ),
b) OR ^{104 where} R ¹⁰⁴ is H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, wherein the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is Optionally substituted with R ¹⁶⁰ ),
c) OCOR ^{105 wherein} R ¹⁰⁵ is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het, the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is optionally in R ¹⁶⁰ May be substituted),
d) SR ¹⁰⁸ , SO ₂ N (R ¹⁰⁸ ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ^{108 wherein} each R ¹⁰⁸ is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ^{108 of the above} are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6- or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het or heterocycle being optionally substituted with R ¹⁶⁰ as required),
e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ¹¹² is H, CN, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, COOR ¹¹⁵ or SO ₂ R ^{115 where} R ¹¹⁵ Is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or ( C _1-6 alkyl) Het), or both R ¹¹¹ and R ¹¹² are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-membered, 6-membered or 7-membered saturated complex. forms a ring, said alkyl, cycloalkyl, aryl, Het, (C _1-6 Alkyl) aryl, optionally substituted with (C _1-6 alkyl) Het R ¹⁶⁰ as needed or heterocycle),
f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) Alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁶⁰ ),
g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- ( C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹¹⁸ is covalently bound to R ¹¹⁹ and they are bound Bonded to nitrogen to form a 5-, 6-, or 7-membered saturated heterocycle, or R ¹¹⁸ and R ¹²⁰ are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6-membered Or a 7-membered saturated heterocycle, the alkyl, cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _{1- 6} alkyl) Het or heterocycle being optionally substituted with R ¹⁶⁰ as required),
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ and R ¹²² are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ), respectively. Cycloalkyl, 6- or 10-membered aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het is optionally substituted with R ¹⁶⁰ , or R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ , wherein R ¹²³ and each R ¹²⁴ is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), or both R ¹²⁴ are covalently bonded together to form a 5-membered, 6 Forming a 7-membered or 7-membered saturated heterocycle, Alkyl, cycloalkyl, alkyl - cycloalkyl, aryl, Het, optionally substituted with (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het and R ¹⁶⁰ by heterocycle necessary),
i) COR ^{127 wherein} R ¹²⁷ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, wherein the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is Optionally substituted with R ¹⁶⁰ ),
j) Tetrazole, COOR ¹²⁸ (wherein R ¹²⁸ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl) , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁶⁰ ), and
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ¹²⁹ and R ¹³⁰ are covalently bonded together and they are bonded Combined with nitrogen to form a 5-, 6- or 7-membered saturated heterocycle, the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) ) Het and heterocycle are optionally substituted with R ¹⁶⁰ ), defined as 1-3 substituents selected from
R ¹⁶⁰ is tetrazole, halogen, CN, C _1-6 alkyl, haloalkyl, COOR ¹⁶¹ , SO ₃ H, SR ¹⁶¹ , SO ₂ R ¹⁶¹ , OR ¹⁶¹ , N (R ¹⁶² ) ₂ , SO ₂ N (R ¹⁶² ) ₂ , NR ¹⁶² COR ¹⁶² or CON (R ¹⁶² ) ₂ defined as one or two substituents, wherein R ¹⁶¹ and each R ¹⁶² are independently H, (C _1-6 ) alkyl , (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, or both R ¹⁶² are covalently bonded together and the nitrogen to which they are bonded To form a 5-, 6-, or 7-membered saturated heterocycle] Formula (II):

Wherein A is O, S or NR ¹ and R ¹ , R ² , R ³ , K, L, M and Z are as defined in claim 1
Compound. A compound according to claim 2 wherein A is NR ¹ .   4. A compound according to claim 3, wherein M, K and L are CH. Formula (III):

Wherein B is NR ³ and R ¹ , R ² , R ³ , K, L, M and Z are as defined in claim 1
Compound.   6. A compound according to claim 5, wherein M, K and L are CH. formula:

Wherein R ¹ , R ² , R ³ and Z are as defined in claim 1
Compound. R ¹ is H, CH _3, selected from isopropyl or isobutyl, a compound according to claim 1. R ¹ is H or CH _3, wherein The compound of claim 8. R ¹ is CH _3, The compound of claim 9. R ² is CON (R ²² ) ₂ , wherein each R ²² is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _5-7 ) cycloalkenyl, 6- or 10-membered aryl or Het, or both R ²² are joined together to form a 5-, 6- or 7-membered saturated heterocycle with the nitrogen to which they are attached, or R ² is H , Halogen, (C _1-6 ) alkyl, haloalkyl, (C _2-6 ) alkenyl, (C _5-7 ) cycloalkenyl, 6-membered or 10-membered aryl or Het, the alkyl, haloalkyl, (C _{2 -6)} alkenyl, (C _5-7) cycloalkenyl, the required respective aryl or Het being optionally substituted with R ^20, R ²⁰ is
1 selected from halogen, NO ₂ , cyano, azide, C (= NH) NH ₂ , C (= NH) NH (C _1-6 ) alkyl or C (= NH) NHCO (C _1-6 ) alkyl ~ 4 substituents, or
a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, (C _2-6 ) alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl (all of which may optionally be substituted with R ¹⁵⁰ ),
b) OR ^{104 where} R ¹⁰⁴ is H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, wherein the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is Optionally substituted with R ¹⁵⁰ ),
c) OCOR ^{105 wherein} R ¹⁰⁵ is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het, the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is optionally R ¹⁵⁰ May be substituted),
d) SR ¹⁰⁸ , SO ₂ N (R ¹⁰⁸ ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ^{108 wherein} each R ¹⁰⁸ is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ^{108 of the above} are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6- or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het or heterocycle may be optionally substituted with R ¹⁵⁰ ),
e) NR ¹¹¹ R ^{112 wherein} R ¹¹¹ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl , Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, and R ¹¹² is H, CN, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) Het, COOR ¹¹⁵ or SO ₂ R ^{115 where} R ¹¹⁵ Is (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or ( C _1-6 alkyl) Het), or both R ¹¹¹ and R ¹¹² are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-membered, 6-membered or 7-membered saturated complex. forms a ring, said alkyl, cycloalkyl, aryl, Het, (C _1-6 Alkyl) aryl or (C _1-6 alkyl) Het, or heterocycle being optionally substituted with R ^0.99 if ^{necessary), f) NR 116 COR 117} ( wherein, R ¹¹⁶ and R ¹¹⁷ are each H, ( C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _{1- 6} alkyl) Het, said (C _1-6) alkyl, (C _3-7) cycloalkyl, (C _1-6) alkyl - (C _3-7) cycloalkyl, aryl, Het, (C _{1- 6} alkyl) aryl or (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- ( C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or R ¹¹⁸ is covalently bound to R ¹¹⁹ and they are bound Bonded to nitrogen to form a 5-, 6-, or 7-membered saturated heterocycle, or ^R119 and ^R120 are covalently bonded together, and bonded to the nitrogen to which they are bonded, 5-membered, 6-membered Or a 7-membered saturated heterocycle, the alkyl, cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _{1- 6} alkyl) Het or heterocycle being optionally substituted with R ^0.99 if necessary),
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ and R ¹²² are H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ), respectively. Cycloalkyl, 6- or 10-membered aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het is optionally substituted with R ¹⁵⁰ , or R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ , wherein R ¹²³ and each R ¹²⁴ is independently H, (C _1-6 alkyl), (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _{1 -6} alkyl) aryl or (C _1-6 alkyl) Het, or R ¹²⁴ is OH or O (C _1-6 alkyl), or both R ¹²⁴ are covalently bonded together to form a 5-membered, 6 Forming a 7-membered or 7-membered saturated heterocycle, Alkyl, cycloalkyl, alkyl - cycloalkyl, aryl, Het, optionally substituted with (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het and R ^0.99 by heterocycle necessary),
i) COR ^{127 wherein} R ¹²⁷ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het , (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the alkyl, cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het is necessary ^Optionally substituted by R ¹⁵⁰ )
j) COOR ^{128 wherein} R ¹²⁸ is H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het , (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, the (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl and (C _1-6 alkyl) Het may be optionally substituted with R ¹⁵⁰ ),
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het, or both R ¹²⁹ and R ¹³⁰ are covalently bonded together and they are bonded Combined with nitrogen to form a 5-, 6- or 7-membered saturated heterocycle, the alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C _1-6 alkyl) aryl, (C _1-6 alkyl) ) Het and heterocycle may be optionally substituted with R ¹⁵⁰ ), l) aryl, Het, (C _1-6 alkyl) aryl or (C _1-6 alkyl) Het (all of which are optionally R ¹⁵⁰ may be substituted)
1 to 4 substituents selected from
R ¹⁵⁰
1 to 3 substituents selected from halogen, NO ₂ , cyano or azide, or
a) (C _1-6 ) alkyl or haloalkyl, (C _3-7 ) cycloalkyl, (C _2-6 ) alkenyl, (C _2-8 ) alkynyl, (C _1-6 ) alkyl- (C _3-7 ) Cycloalkyl (all of which may optionally be substituted with R ¹⁶⁰ ),
b) OR ¹⁰⁴ (wherein R ¹⁰⁴ is H, (C _1-6 alkyl) or (C _3-7 ) cycloalkyl, and the alkyl or cycloalkyl may be optionally substituted with R ¹⁶⁰ ) ,
d) SR ¹⁰⁸ , SO ₂ N (R ¹⁰⁸ ) ₂ or SO ₂ N (R ¹⁰⁸ ) C (O) R ^{108 wherein} each R ¹⁰⁸ is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _1-6 ) alkyl- (C _3-7 ) cycloalkyl, aryl, Het, or both R ¹⁰⁸ are covalently bonded together and the nitrogen to which they are bonded 5- coupled to form a 6-membered or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, optionally substituted with R ¹⁶⁰ by Het and heterocycle necessary),
e) NR ¹¹¹ R ^{112 where} R ¹¹¹ is H, (C _1-6 ) alkyl, or (C _3-7 ) cycloalkyl, and R ¹¹² is H, (C _1-6 ) alkyl or ( C _3-7 ) cycloalkyl, COOR ¹¹⁵ or SO ₂ R ^{115 where} R ¹¹⁵ is (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl, or R ¹¹¹ and R ¹¹² Are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6-, or 7-membered saturated heterocycle, wherein the alkyl, cycloalkyl, and heterocycle are optionally R ¹⁶⁰ May be substituted),
f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl, the (C _1-6 ) alkyl and (C _{3 -7} ) cycloalkyl may optionally be substituted with R ¹⁶⁰ ),
g) NR ¹¹⁸ CONR ¹¹⁹ R ^{120 wherein} R ¹¹⁸ , R ¹¹⁹ and R ¹²⁰ are each H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl, or R ¹¹⁸ is R ¹¹⁹ Bonded to the nitrogen to which they are bonded to form a 5-membered, 6-membered or 7-membered saturated heterocycle, or ^R119 and ^R120 are covalently bonded together and they are bonded 5- has been joined to the nitrogen which are to form a 6-membered or 7-membered saturated heterocycle, said alkyl, optionally substituted with R ¹⁶⁰ by cycloalkyl, and heterocyclic are required),
h) NR ¹²¹ COCOR ^{122 wherein} R ¹²¹ is H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl, and the alkyl and cycloalkyl may be optionally substituted with R ¹⁶⁰ Well, or R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ , wherein R ¹²³ and each R ¹²⁴ is independently H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl. Or both R ¹²⁴ are covalently bonded together to form a 5-, 6-, or 7-membered saturated heterocycle, wherein the alkyl, cycloalkyl, and heterocycle may be optionally substituted with R ¹⁶⁰ ) ,
i) COR ¹²⁷ (wherein R ¹²⁷ is H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl, and the alkyl and cycloalkyl may be optionally substituted with R ¹⁶⁰ ) ,
j) COOR ^{128 wherein} R ¹²⁸ is H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl, and (C _1-6 ) alkyl and (C _3-7 ) cycloalkyl are Optionally substituted with R ¹⁶⁰ ), and
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl or (C _3-7 ) cycloalkyl, or both R ¹²⁹ and R ¹³⁰ together Covalently bonded to the nitrogen to which they are attached to form a 5-, 6-, or 7-membered saturated heterocycle, wherein the alkyl, cycloalkyl, and heterocycle may be optionally substituted with R ¹⁶⁰ Good),
1 to 3 substituents selected from
R ¹⁶⁰ is selected from halogen, CN, C _1-6 alkyl, haloalkyl, COOR ¹⁶¹ , OR ¹⁶¹ , N (R ¹⁶² ) ₂ , SO ₂ N (R ¹⁶² ) ₂ , NR ¹⁶² COR ¹⁶² or CON (R ¹⁶² ) ₂ R ¹⁶¹ and each R ¹⁶² is independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl or (C _{1- 6} ) Alkyl- (C _3-7 ) cycloalkyl, or both R ¹⁶² are covalently bonded together and bonded to the nitrogen to which they are bonded to form a 5-, 6- or 7-membered saturated heterocycle The compound of claim 1, which forms R ² is selected from aryl or Het, each optionally halogen, haloalkyl, N ₃ , or
a) (C _1-6 ) alkyl, optionally substituted with OH, or O (C _1-6 ) alkyl,
b) (C _1-6 ) alkoxy,
e) NR ¹¹¹ R ^{112 wherein} both R ¹¹¹ and R ¹¹² are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or R ¹¹² is 6 or 10 members Aryl, Het, (C _1-6 ) alkyl-aryl or (C _1-6 ) alkyl-Het, or both R ¹¹¹ and R ¹¹² are covalently bonded together and to the nitrogen to which they are bonded. Bonded to form a nitrogen-containing heterocycle, each of said alkyl, cycloalkyl, aryl, Het, alkyl-aryl or alkyl-Het is optionally halogen or —OR ^2h or N (R ^2h ) ₂ (wherein each R ^2h is independently H, (C _1-6 ) alkyl, or both R ^2h are covalently bonded together and bound to the nitrogen to which they are attached to form a nitrogen-containing heterocycle) May be substituted)
f) NHCOR ^{117 where} R ¹¹⁷ is (C _1-6 ) alkyl;
i) CO-aryl, and
k) Mono- or di-substituted with a substituent selected from the group consisting of CONH ₂ , CONH (C _1-6 alkyl), CON (C _1-6 alkyl) ₂ , CONH-aryl, or CONHC _1-6 alkylaryl 12. The compound of claim 11, which may be R ² is aryl or Het, each optionally halogen, haloalkyl, or
a) (C _1-6 ) alkyl, optionally substituted with OH, or O (C _1-6 ) alkyl,
b) (C _1-6 ) alkoxy, and
e) NR ¹¹¹ R ^{112 wherein} both R ¹¹¹ and R ¹¹² are independently H, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, or R ¹¹² is 6 or 10 members Aryl, Het, (C _1-6 ) alkyl-aryl or (C _1-6 ) alkyl-Het, or both R ¹¹¹ and R ¹¹² are covalently bonded together and to the nitrogen to which they are bonded. Bonded to form a nitrogen-containing heterocycle, each of said alkyl, cycloalkyl, aryl, Het, alkyl-aryl or alkyl-Het is optionally halogen or —OR ^2h or N (R ^2h ) ₂ (wherein each R ^2h is independently H, (C _1-6 ) alkyl, or both R ^2h are covalently bonded together and bound to the nitrogen to which they are attached to form a nitrogen-containing heterocycle) May be substituted)
The compound according to claim 12, which may be mono- or di-substituted with a substituent selected from the group consisting of: R ² is phenyl or

14. A compound according to claim 13, which is a heterocycle selected from: all of which are optionally substituted as defined in claim 13. R ² is H, Br, CONHCH ₃ , CON (CH ₃ ) ₂ , CONH ₂ , CH = CH ₂ ,

The compound of claim 1 selected from the group consisting of: R ² is

16. A compound according to claim 15, selected from: R ² is

17. A compound according to claim 16 selected from. The compound according to claim 1, wherein R ³ is (C _3-7 ) cycloalkyl. The compound according to claim 18, wherein R ³ is cyclopentyl or cyclohexyl. The compound of claim 1, wherein Y ¹ is O. Z is N (R ^6a ) R ⁶ where R ^6a is H and R ⁶ is (C _2-6 ) alkenyl, aryl, Het, (C _1-6 ) alkyl-aryl, (C _1-6 ) Alkyl-Het, the alkenyl, aryl, Het, alkyl-aryl or alkyl-Het are all optionally
a) (C _1-6 ) alkyl, C _3-7 spirocycloalkyl or (C _2-6 ) alkenyl optionally containing one or two heteroatoms (all of which are optionally R ¹⁵⁰ May be substituted)
b) OR ¹⁰⁴ (wherein R ¹⁰⁴ is H or (C _1-6 alkyl), and the alkyl may be optionally substituted with R ¹⁵⁰ ),
e) NR ¹¹¹ R ¹¹² (wherein R ¹¹¹ is H or (C _1-6 ) alkyl and R ¹¹² is (C _1-6 ) alkyl or aryl), and the alkyl and aryl are optionally R ¹⁵⁰ may be substituted)
i) COR ¹²⁷ (wherein R ¹²⁷ is H),
j) COOR ¹²⁸ (where R ¹²⁸ is H),
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, aryl or Het, wherein said alkyl, aryl and Het are optionally substituted with R ¹⁵⁰ May be)
l) Aryl or Het (all of which may optionally be substituted with R ¹⁵⁰ )
May be substituted with 1 to 4 substituents selected from
R ¹⁵⁰
a) (C _1-6 ) alkyl or (C _2-6 ) alkenyl (all of which may optionally be substituted with R ¹⁶⁰ ),
e) NR ¹¹¹ R ¹¹² (wherein R ¹¹¹ is H and R ¹¹² is H),
j) COOR ¹²⁸ (where R ¹²⁸ is H), and
k) CONR ¹²⁹ R ¹³⁰ (wherein R ¹²⁹ and R ¹³⁰ are independently H),
Selected from 1 to 3 substituents selected from
The R ¹⁶⁰ is defined as one or two substituents selected from COOR ¹⁶¹ or CON (R ¹⁶² ) ₂ , wherein R ¹⁶¹ and each R ¹⁶² is independently H. Compound. R ⁶ is C _2-6 alkenyl, phenyl, (C _1-6 ) alkyl-aryl, (C _1-6 ) alkyl-Het, and the alkyl part of the alkenyl, phenyl and alkyl-aryl or alkyl-Het is If necessary
a) (C _1-6 ) alkyl, C _3-7 spirocycloalkyl optionally containing one or two heteroatoms, (C _2-6 ) alkenyl (all of which are optionally C _1-6 Optionally substituted with alkyl or NH ₂ ),
e) NHR ¹¹² (wherein R ¹¹² is aryl, which aryl may be optionally substituted with R ¹⁵⁰ ),
j) COOH,
k) CONR ¹²⁹ R ^{130 wherein} R ¹²⁹ and R ¹³⁰ are independently H, (C _1-6 ) alkyl, aryl or Het, and the alkyl, aryl and Het are optionally substituted with R ¹⁵⁰ May be)
l) Phenyl or Het (both optionally substituted with R ¹⁵⁰ )
It may be substituted with 1-3 substituents selected from and R ^0.99 is
a) (C _1-6 ) alkyl or (C _2-6 ) alkenyl (both optionally substituted with COOH or CONH ₂ ),
j) COOH, and
k) CONH ₂
The compound according to claim 21, which is selected from one or two substituents selected from: Z is

The compound according to claim 1, which is selected from: R ⁶ is

In which R ⁷ and R ⁸ are each independently H or (C _1-6 ) alkyl, said alkyl optionally substituted with R ⁷⁰ , or
R ⁷ and R ⁸ are covalently bonded together to form a _4- , 5- or 6-membered heterocycle having a second (C _3-7 ) cycloalkyl or one heteroatom selected from O, N and S Forming a ring,
R ⁷⁰
e) NR ¹¹¹ R ^{112 where} R ¹¹¹ is H or (C _1-6 ) alkyl and R ¹¹² is H or (C _1-6 ) alkyl;
The compound of claim 1, wherein R ⁷ and R ⁸ are each independently H or (C _1-6 ) alkyl, or R ⁷ and R ⁸ are covalently bonded together to produce cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidine, piperidine, tetrahydrofuran, tetrahydropyran, Or form pentamethylene sulfide,
If the alkyl is necessary
b) NH ₂ or N (CH ₂ CH) ₂
25. The compound of claim 24, which may be mono-substituted with a substituent selected from: R ⁷ and R ⁸ are

Or R ⁷ and R ⁸ together

26. The compound of claim 25, wherein: R ⁷ and R ⁸ are

27. The compound of claim 26, selected from: R ⁹ is H, claim 24 A compound according. Q is 6 or 10 membered aryl, Het or (C _1-6 alkyl) aryl, all of which are optionally
-One substituent selected from halogen or cyano, or
a) (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _2-6 ) alkenyl or (C _2-8 ) alkynyl (all of which may optionally be substituted with R ¹⁵⁰ ),
b) OR ¹⁰⁴ (where R ¹⁰⁴ is H),
d) SO ₂ N (R ¹⁰⁸ ) ₂ (where each R ¹⁰⁸ is independently H),
e) NR ¹¹¹ R ^{112 where} R ¹¹¹ is H or (C _1-6 ) alkyl and R ¹¹² is H or (C _1-6 ) alkyl;
f) NR ¹¹⁶ COR ^{117 wherein} R ¹¹⁶ and R ¹¹⁷ are each H or (C _1-6 ) alkyl.
h) NR ¹²¹ COCOR ^{122 where} R ¹²¹ is H and R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ , wherein R ¹²³ and each R ¹²⁴ are independently H or (C _1-6 alkyl), or R ¹²⁴ is OH),
j) COOR ¹²⁸ (where R ¹²⁸ is H),
k) CONR ¹²⁹ R ¹³⁰ (wherein R ¹²⁹ and R ¹³⁰ are independently H),
l) Het (optionally substituted with R ¹⁵⁰ )
May be substituted with 1 to 4 substituents selected from
R ¹⁵⁰
1 substituent which is -cyano, or
e) NR ¹¹¹ R ¹¹² (wherein R ¹¹¹ is H and R ¹¹² is H),
j) Tetrazole or COOR ¹²⁸ (wherein R ¹²⁸ is H), and
k) CONR ¹²⁹ R ¹³⁰ (wherein R ¹²⁹ and R ¹³⁰ are independently H),
The compound according to claim 24, which is selected from 1 to 3 substituents selected from: Q is 6- or 10-membered aryl or Het, both of which are optional
-Halogen or cyano, or
a) (C _1-6 ) alkyl, primary (C _3-7 ) cycloalkyl, (C _2-6 ) alkenyl or (C _2-8 ) alkynyl (all of which are optionally substituted with R ¹⁵⁰ You may)
b) OR ¹⁰⁴ (where R ¹⁰⁴ is H),
d) SO ₂ NHR ¹⁰⁸ (where R ¹⁰⁸ is H),
e) NR ¹¹¹ R ¹¹² where both R ¹¹¹ and R ¹¹² are independently H or (C _1-6 ) alkyl.
f) NHCOR ¹¹⁷ (wherein R ¹¹⁷ is H or (C _1-6 ) alkyl),
h) NHCOCOR ^{122 where} R ¹²² is OR ¹²³ or N (R ¹²⁴ ) ₂ , wherein R ¹²³ and each R ¹²⁴ is independently H or (C _1-6 alkyl)),
j) COOR ¹²⁸ (where R ¹²⁸ is H),
k) CONHR ¹³⁰ (where R ¹³⁰ is H),
l) Het (the Het may be optionally substituted with R ¹⁵⁰ )
May be substituted with 1 to 3 substituents selected from
R ¹⁵⁰
e) NR ¹¹¹ R ¹¹² (wherein both R ¹¹¹ and R ¹¹² are independently H),
j) COOR ¹²⁸ (where R ¹²⁸ is H), and
k) CONHR ¹³⁰ (where R ¹³⁰ is H)
30. The compound of claim 29, selected from 1 to 3 substituents selected from: Q is

30. The compound of claim 29, selected from: Q is

32. The compound of claim 31, selected from: Formula Ia:

Or a salt thereof.
[Where,
A is O, S, NR ¹ , or CR ¹ ;
B is NR ³ or CR ^3, where with the proviso that one of A or B is CR ¹ or CR ^3,
R ¹ is (C _1-6 alkyl) -5-membered or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from H, (C _1-6 ) alkyl, benzyl, and O, N, and S Selected from the group consisting of
The benzyl and the heterocycle may be optionally substituted with 1 to 4 COOH,
R ² is 5-membered or 6-membered having 1 to 4 heteroatoms selected from H, halogen, (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, phenyl, O, N, and S Selected from the group consisting of heterocycles, pyridine-N-oxides, and 9- or 10-membered bicyclic heterocycles having 1 to 4 heteroatoms selected from O, N and S;
The phenyl, heterocycle and bicyclic heterocycle are optionally halogen, C (halogen) ₃ , (C _1-6 ) alkyl, OH, O (C _1-6 alkyl), NH ₂ , and N (C _{1- (6} alkyl) optionally substituted with 1 to 4 substituents selected from the group consisting of ₂ ;
R ³ is (C _3-7 ) cycloalkyl,
M is N or CR ⁴ where R ⁴ is H;
K and L are CH,
----- represents a single bond or a double bond,
Y is O or S;
Z is NR ⁶ R ^6a ,
R ⁶ is (C _1-6 ) alkyl, (C _3-6 ) cycloalkyl, (C _6-10 ) aryl, (C _6-10 ) aryl (C _1-6 ) alkyl, (C _2-6 ) alkenyl , (C _3-6 ) cycloalkyl (C _2-6 ) alkenyl, and (C _1-6 ) alkyl-5 or 6 atom heterocycle having 1 to 4 heteroatoms selected from O, N and S And
The cycloalkyl, aryl, alkenyl, and heterocycle are all optionally 5 or 6-membered heterocycle having 1 to 4 heteroatoms selected from COOH, (C _1-6 ) alkyl, and O, N and S. (The alkyl and heterocycle may be optionally substituted with 1 to 4 substituents selected from (C _1-6 alkyl), NH ₂ and N (C _1-6 alkyl) ₂ ),
A 9-membered or 10-membered bicyclic heterocycle having 1 to 4 heteroatoms selected from O, N and S (the bicyclic heterocycle is (C _2-4 alkenyl) COOH, OH and —O— (C _1-6 ) may be substituted with 1 to 4 substituents selected from alkylCOOH),
6-membered aryl optionally substituted with 1 to 4 substituents selected from (C _2-4 alkenyl) COOH and (C _1-4 ) alkoxy, if necessary,
May be substituted with 1 to 4 substituents selected from
The alkyl is
5- or 6-membered heterocycle containing 1 to 4 heteroatoms selected from the group consisting of O, N and S (wherein the heterocycle is (C _1-6 alkyl), NH ₂ and N (C _1-6 alkyl) ) May be substituted with 1 to 4 substituents selected from the group consisting of ₂ );
A 9-membered or 10-membered bicyclic heterocycle containing 1 to 4 heteroatoms selected from the group consisting of O, N and S (the bicyclic heterocycle is (C _2-4 alkenyl) COOH, OH and And optionally substituted with 1 to 4 substituents selected from the group consisting of —O— (C _1-6 ) alkylCOOH);
6-membered aryl ( which may be substituted with 1 to 4 substituents selected from the group consisting of (C _2-4 alkenyl) COOH and (C _1-4 ) alkoxy),
Substituted with 1 to 4 substituents selected from the group consisting of:
R ^6a is H, or
R ⁶

And
Where
W is CR ⁷ R ⁸ and R ⁷ and R ⁸ are each independently H or (C _1-6 alkyl), or
R ⁷ and R ⁸ are covalently bonded together (C _3-7 cycloalkyl) and have a 4-, 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N, and S Form or
One of R ⁷ or R ⁸ is covalently bonded to R ⁹ to form pyrrolidine;
The alkyl, cycloalkyl and heterocycle are optionally substituted with 1 to 4 substituents selected from the group consisting of (C _1-6 alkyl), NH ₂ and N (C _1-6 alkyl) _2. Well,
R ⁹ is H, and Q is selected from 5-membered or 6-membered heterocycle having 1-4 heteroatoms selected from 6-membered aryl, O, N, and S, O, N, and S A 9- or 10-membered bicyclic heterocycle having 1 to 4 heteroatoms,
(All the aryl, heterocycle and bicyclic heterocycles are optionally OH, COOH, (C _1-6 ) alkyl, (C _1-6 ) alkyl COOH, (C _1-6 alkyl) (C _2-4 alkynyl) ), Halogen, (C _2-4 ) alkenyl, O, N, and S 1 to 4 substituents selected from 5 or 6 membered second heterocycles having 1 to 4 heteroatoms Optionally substituted with a group
The second heterocyclic ring may be optionally substituted with 1 to 4 substituents selected from COOH and NH ₂ ),
Sulfonamide, —CONH ₂ , (C _2-4 alkenyl) COOH (wherein the alkenyl may be optionally substituted by 1 to 2 (C _1-6 alkyl) substituents),
Tetrazolyl, NH ₂ , —O (C _1-6 alkyl) COOH, cyano, —NHCOCOOH, —NHCOCONHOH, —NHCOCONH ₂ , —NHCOCONHCH, NH (C _1-6 alkyl) ₂ , —NH (C _2-4 ) acyl Selected from the group consisting of formula:

Compound.
[Wherein A, R ² , R ³ and Z are as defined below.

] formula:

Compound.
[Wherein R ¹ , R ² , R ⁷ , R ⁸ and Q are as defined below.

] formula:

Compound.
[Wherein R ¹ , R ³ , R ⁷ and R ⁸ are as defined below.

] formula:

Compound.
[Wherein R ¹ , R ³ , R ⁷ and R ⁸ are as defined below.

] formula:

Compound.
[Wherein R ² , R ³ and n are as defined below.

] formula:

Compound.
[Wherein R ¹ , R ² , R ⁷ and R ⁸ are as defined below.

] formula:

Compound.
[Wherein R ² , R ⁷ , R ⁸ and Q are as defined below.

] formula:

Compound.
[Wherein A, R ² , R ⁷ and R ⁸ are as defined below.

] formula:

Compound.
[Wherein R ² , R ⁷ and R ⁸ are as defined below.

]   A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, as an inhibitor of the RNA-dependent RNA polymerase activity of the enzyme NS5B encoded by HCV.   2. A compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof as an inhibitor of HCV replication.   A pharmaceutical composition for the treatment or prevention of HCV infection, comprising an effective amount of a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.   46. The composition of claim 45, further comprising an immunomodulator.   47. The composition of claim 46, wherein said immunomodulator is selected from [alpha]-, [beta]-, [delta]-, [gamma]-, and [omega] -interferon.   46. The composition of claim 45, further comprising another antiviral agent.   49. The composition of claim 48, wherein the antiviral agent is selected from ribavirin and amantadine.   46. The composition of claim 45, further comprising another inhibitor of HCV polymerase.   46. The composition of claim 45, further comprising an inhibitor of HCV helicase, HCV protease, HCV metalloprotease or HCV IRES.   Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment of HCV infection. Formula 1c:

Wherein A, R ² , B, K, L, M, R ⁷ and R ⁸ are as defined in claim 1
The intermediate compound represented by these, or its salt. a) a coupling agent in a mixture with or without an aprotic solvent at a temperature between 20 ° C. and 170 ° C., and intermediate 1c:

Is coupled with an amine Q-NH ₂ to form a compound of formula I wherein A, R ² , B, R ⁷ , R ⁸ , Q, K, L, M and Q are as defined in claim 1 A process for the preparation of a compound of formula I according to claim 1 , characterized in that